The Ethical Challenge Posed by Acquired

ISSN 1473-9348 Volume 8 Issue 2 May/June 2008
ACNR www.acnr.co.uk
Advances in Clinical Neuroscience & Rehabilitation
Paul Reading
The Neurological Sleep Clinic – Part 2 – Insomnia and parasomnias
Declan Chard and David Miller

Magnetic Resonance Imaging in Multiple Sclerosis – A Brief Review
Reuben Johnson and Hilary Madder

Prevention and Treatment of Vasospasm following Subarachnoid
Haemorrhage
Conference News • Journal Reviews • Book Reviews • Diary of Events

Contents
Editorial board and contributors

Roger Barker is co-editor of ACNR, and is Honorary Consultant in
Neurology at The Cambridge Centre for Brain Repair. His main area
of research is into neurodegenerative and movement disorders, in
particular parkinson's and Huntington's disease. He is also the univer-
Contents May/June 2008
sity lecturer in Neurology at Cambridge where he continues to devel-
op his clinical research into these diseases along with his basic
research into brain repair using neural transplants. 4 Editorial
Alasdair Coles is co-editor of ACNR. He has recently been appoint-
ed to the new position of University Lecturer in Neuroimmunology 6 Review Article
at Cambridge University. He works on experimental immunological The Neurological Sleep Clinic – Part 2 – Insomnia and Parasomnias
therapies in multiple sclerosis. Paul Reading
8 Review Article
Stephen Kirker is the editor of the Rehabilitation Section of ACNR
and Consultant in Rehabilitation Medicine in Addenbrooke's NHS
Declan Chard, David Miller
Trust, Cambridge. He trained in neurology in Dublin, London and
Edinburgh before moving to rehabilitation in Cambridge and 12 Rehabilitation Article
Norwich. His main research has been into postural responses after The Ethical Challenge Posed by Acquired Brain Injury
stroke. His particular interests are in prosthetics, orthotics, gait train- Joanna Collicutt McGrath
ing and neurorehabilitation.
David J Burn is the editor of our Conference News Section and is
14 Neurophysiology Article
Professor in Movement Disorder Neurology & Honorary Consultant, Evoked Potentials and the Prognosis of Comatose Patients Receiving
Newcastle General Hospital. He runs Movement Disorders clinics in Intensive Care
Newcastle-upon-Tyne. Research interests include progressive Nick Kane
supranuclear palsy and dementia with Lewy bodies. He is also
involved in several drugs studies for Parkinson's Disease. 16 Neuropathology Article
The Significance of Diffuse Axonal Injury: how to diagnose it and
Andrew Larner is the editor of our Book Review Section. He is a
what does it tell us?
Consultant Neurologist at the Walton Centre for Neurology and
Neurosurgery in Liverpool, with a particular interest in dementia
Tibor Hortobágyi and Safa Al-Sarraj
and cognitive disorders. He is also an Honorary Apothecaries'
Lecturer in the History of Medicine at the University of Liverpool. 20 Neurology and Literature
‘Neurological Literature’: Cognitive Disorders
Andrew J Larner
Alastair Wilkins is our Case Report Co-ordinator. He is Senior
Lecturer in Neurology and Consultant Neurologist, University of
22 Neurology in India
Bristol. He trained in Neurology in Cambridge, Norwich and Movement Disorders in India
London. His research interests are the basic science of axon Uday Muthane
degeneration and developing treatments for progressive multiple
sclerosis. 24 ABNT
(Association of British Neurologist Trainees)
Nicki Cohen is ACNR’s Neuropathology Editor. She is a Specialist Message from the Chair
Registrar in Neuropathology at Southampton and has a DPhil in Andrew Kelso
Neuroscience. She is Chair of the Trainee’s Advisory Committee at the
Royal College of Pathologists and Neuropathology trainee represen-
tative. Her research interests lie in CNS stem cell biology, and the
26 Neurosurgery Article
brain’s response to injury. Prevention and Treatment of Vasospasm Following Subarachnoid
Haemorrhage
Reuben Johnson, Hilary Madder
Peter Whitfield is ACNR’s Neurosurgery Editor. He is a Consultant
Neurosurgeon at the South West Neurosurgery Centre, Plymouth.
His clinical interests are wide including neurovascular conditions, 30 Case Report
head injury, stereotactic radiosurgery, image guided tumour sur- Spontaneous Anterior Intracranial Artery Dissection:
gery and lumbar microdiscectomy. He is an examiner for the MRCS An Important Cause of Stroke in Young People
and is a member of the SAC in neurosurgery. Gina Kennedy, Paddy Ruane, Shelly Renowden, David Cottrell
32 Book Reviews
International editorial liaison committee
36 Events Diary
38 Conference News
43 Journal Reviews
Professor Riccardo Professor Klaus Professor Hermann Professor Nils Erik
Soffietti, Italy: Berek, Austria: Stefan, Germany: Gilhus, Norway: 45 News Review
Chairman of the Head of the Professor of Professor of
Neuro-Oncology
Service, Dept of
Neurological
Department of the
Neurology
/Epileptology in the
Neurology at the
University of Bergen
47 Awards and Appointments
Neuroscience and KH Kufstein. Department of and Haukeland
Oncology, University Neurology, University University Hospital.
ERRATUM: The book review of "Understanding Neurology - A Problem Oriented Approach" by
and S. Giovanni Erlangen-Nürnberg. John Greene and Ian Bone published in ACNR 2008;8(1):51 was by John Bowen, not by Andrew Larner.
Battista Hospital. Apologies to the authors of both the book and the reviewer for this error.
ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I3

Editorial
O
ver the last 10-15 years it has become increas- In our series from India, Uday Muthane describes
ingly clear that the problem with MS is more the causes of the different types of movement disor-
than just one of areas of inflammation, demyeli- ders seen in this part of the world. He also discuss-
nation and then repair. The early loss of axons coupled es the challenges of managing such cases, in terms
to the widespread pathology consequent on early of the availability of diagnostic tests and therapeu-
inflammation has challenged those working in the field tic options and the problem that the vast majority
as to how best to treat this condition and then how best of individuals have no means of paying for such
to measure any effect from such therapies. Declan treatments.
Chard and David Miller, in their beautifully succinct Andrew Larner, after four excellent articles on
article, discuss the power of MRI in this process, both in headache, takes us into the world of cognition and
terms of what it has been able to show and what it may literature. As usual this is a highly entertaining
be used for in the future. This article highlights how account with plenty to reflect on.
technical developments for research can translate into Nick Kane, in his contribution to the
more mainstream clinical practice. Neurophysiology series, edited by Andrew Michell,
Our other major review article is the second in his discusses the role of evoked potentials and other
series on the Neurological Sleep Clinic by Paul Reading neurophysiological tests in the evaluation of
and tackles the insomnias and parasomnias. He discusses, again from a comatosed patient and their utility as tools for prognosis. He concludes
personal perspective, the therapeutic options and useful discriminators in that they are probably underused, as are all neurophysiological tests,
distinguishing the causes of these types of sleep disorder. probably underused in the ITU setting with patients who have prolonged
There are some articles which we publish that cause me to stop and coma states. The ease with which such neurophysiological tests could be
think about greater questions than just treatments in patients with neu- used does make them attractive tools of assessment with the caveat that it
rological problems. One such article by Joanna Collicut does just this, as requires experience and expertise to interpret them accurately.
it engages with the ethical challenges posed by acquired brain injury. In our ENS supplement, Steven Laureys and colleagues gives us anoth-
Whilst we have discussed the problems in patients in a vegetative state in er article on the challenge in accurately assessing patients with prolonged
other issues of ACNR, this article takes the debate to a wider remit. It is a abnormalities in consciousness and awareness. The critical importance of
fascinating read about some of the current dilemmas and problems that diagnosing the vegetative state over a minimally conscious state or locked
face medical practitioners dealing with such patients and I strongly urge in syndrome cannot be over emphasised and in their review Laureys et al
you to read this article given its thought provoking content. demonstrate how this field has progressed using functional imaging and
This article in our Neuropathology series by Tibor Hortobagyi and Safa neurophysiology.
Al-Sarraj, discusses the best ways to stain for axonal injury and how this Also don’t forget our case reports which this month features a fascinat-
can be used to ascertain the cause of that pathology. In particular, APP ing case of a spontaneous anterior intracranial artery dissection by Gina
immunohistochemistry seems an especially sensitive tool for detecting Kennedy and colleagues, along with a new case of CNS vasculitis from
damaged axons and its use is becoming more mainstream and, with this, Nick Gutowski et al. We also have our usual series of reviews, including a
its utility in establishing the cause of diffuse axonal injury. wonderful update on Muscular Dystrophies by Rajith de Silva in the con-
One of the major problems in those surviving their initial subarach- ference report section which also features a picture of our very own Dr
noid haemorrhage is subsequent vasospasm that occurs in most cases and Alasdair Coles. So I hope you continue to enjoy ACNR and do let us know
which has a significant effect on outcome. In their article in the how we can do things better.
Neurosurgery series Rueben Johnson and Hilary Madder discuss the opti-
mal management of this aspect of subarachnoid haemorrhage and the Roger Barker, Co-Editor,
challenges that such management presents. Email: roger@acnr.co.uk
UWE Artist illuminates Alzheimer’s Disease from Scientific and Artistic Perspectives
The front cover artwork is one of a series created by Jan Martin for a project for Alzheimer’s week in October 2007. Jan was one of a
group of artists from the University of the West of England (UWE) working alongside a team from Bristol University, and BRACE
(Bristol Research into Alzheimers and Care for the Elderly), to explore and illuminate Alzheimer’s disease from scientific and artistic
perspectives. The project culminated in the ‘Remember Me’ exhibition at Bristol’s Create Centre.
Jan’s artwork aims to capture the poignancy of the individual story, while exploring the common experience of memory. Using the
emotional charge which memory carries, she tries to encourage empathy with an individual subject by evoking a sense of common
human experience. Sculpting the face from elements of a person’s life helps to illuminate their history and create a feeling of
empathy, both on an individual and human level.
Jan welcomes private portrait commissions and illustration briefs around this theme.
Jan Martin
For more information contact: E. jan@janmartin.co.uk • W. www.janmartin.co.uk • T. +44 (0)117 908 1675 • m: 44 (0)7905 273933
ISSN 1473-9348 Volume 8 Issue 2 May/June 2008
ACNR is published by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ.
Publisher: Rachael Hansford • Email: rachael@acnr.co.uk
Advertising and Editorial: Patricia McDonnell

Email: patriciamcdonnell@btinternet.com
ACNR www.acnr.co.uk
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Copyright: All rights reserved; no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or
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er or a license permitting restricted photocopying issued in the UK by the Copyright Licensing Authority.
Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by any person acting or refraining from
action as a result of material in or omitted from this magazine. Any new methods and techniques described involving drug usage
should be followed only in conjunction with drug manufacturers' own published literature. Paul Reading
This is an independent publication - none of those contributing are in any way supported or remunerated by any of the companies The Neurological Sleep Clinic – Part 2 – Insomnia and parasomnias
Declan Chard and David Miller

advertising in it, unless otherwise clearly stated. Comments expressed in editorial are those of the author(s) and are not necessarily Magnetic Resonance Imaging in Multiple Sclerosis – A Brief Review Cover picture shows artwork
endorsed by the editor, editorial board or publisher. The editor's decision is final and no correspondence will be entered into. Prevention and Treatment of Vasospasm following Subarachnoid
Haemorrhage
created by Jan Martin as
Conference News • Journal Reviews • Book Reviews • Diary of Events described above.
4 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

I’m going to win.
®
One AED,
many lives
Destination Freedom
ABBREVIATED PRESCRIBING INFORMATION 1,000 mg daily did not affect the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel).
(Please consult the Summary of Product Characteristics (SPC) before prescribing.) Levetiracetam 2,000 mg daily did not affect the pharmacokinetics of digoxin and warfarin and prothrombin
KEPPRA® film-coated tablets 250 mg, 500 mg, 750 mg, 1000 mg times were not modified. Pregnancy and lactation: Should not be used during pregnancy unless clearly
KEPPRA® 100 mg/ml oral solution necessary. Breast-feeding not recommended. Driving, etc: Caution recommended when performing skilled
KEPPRA® 100 mg/ml concentrate for solution for infusion tasks, e.g. driving vehicles or operating machinery. Adverse Effects: Incidence of undesirable effects
Active Ingredient: Tablets: levetiracetam 250, 500, 750 and 1,000 mg. Oral Solution: levetiracetam 100 mg considered to be at least possibly related in controlled clinical studies: Very common (≥10%): asthenia/fatigue,
per ml. Infusion: levetiracetam 100 mg per ml. Uses: Monotherapy for partial onset seizures with or without somnolence. Common (between 1%–10%): GI disturbances, anorexia, weight increase, accidental injury,
secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy. Adjunctive therapy headache, dizziness, hyperkinesia, tremor, ataxia, convulsion, amnesia, balance disorder, disturbances in
for partial onset seizures with or without secondary generalisation in adults and children from 4 years of age, attention, memory impairment, emotional lability/mood swings, hostility, depression, insomnia, nervousness/
for myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy and irritability, agitation, personality disorders, thinking abnormal, vertigo, rash, eczema, pruritus, diplopia, vision
for primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic blurred, myalgia, infection, nasopharyngitis, cough increased, thrombocytopenia. Consult SPC in relation to
Generalised Epilepsy. Infusion: an alternative for patients when oral administration is temporarily not feasible. other side effects. Pharmaceutical Precautions: Tablets: None. Oral solution: Store in original container.
Dosage and Administration: Oral solution should be diluted prior to use. Infusion: Keppra concentrate must After first opening use within 2 months. Infusion: Use immediately after dilution. Legal Category: POM.
be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15 minute infusion. Marketing Authorisation Numbers: 250 mg x 60 tabs: EU/1/00/146/004. 500 mg x 60 tabs: EU/1/00/146/010.
Monotherapy (adults and adolescents from 16 years): Recommended starting dose of 250 mg twice daily which 750 mg x 60 tabs: EU/1/00/146/017. 1,000 mg x 60 tabs: EU/1/00/146/024. Solution x 300 ml: EU/1/146/027,
should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be Infusion (500 mg/5 ml) x 10 vials: EU/1/00/146/030. NHS Cost: 250 mg x 60 tabs: £29.70. 500 mg x 60 tabs:
further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum £52.30. 750 mg x 60 tabs: £89.10. 1,000 mg x 60 tabs: £101.10. Solution x 300 ml: £71.00, Infusion (500 mg/
dose is 1500 mg twice daily. Adjunctive therapy: Adults and adolescents older than 12 years or weighing 50 5ml) x 10 vials: £135.00. Name and Addressof PL Holder: UCB S.A., Allée de la Recherche 60, B-1070
kg or more: 500 mg twice daily can be increased up to 1,500 mg twice daily. Dose changes can be made in Bruxelles, Belgium. Further information is available from: UCB Pharma Ltd., 208 Bath Road, Slough,
500 mg twice daily increases or decreases every two to four weeks. Elderly: Adjustment of the dose is Berkshire, SL1 3WE. Tel: 01753 534655. Fax: 01753 536632. Email: medicalinformationuk@ucb-group.com
recommended in patients with compromised renal function. Children aged 4 to 11 years and adolescents (12 Date of Revision: October 2007
to 17 years) of less than 50 kg: 10 mg/kg twice daily, increased up to 30 mg/kg twice daily. Do not exceed Keppra is a registered trade name.
increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
(For full dosage recommendations see SPC.) Patients with renal impairment: Adjust dose according to
creatinine clearance as advised in SPC. Patients with hepatic impairment: No dose adjustment with mild to Information about adverse event reporting can be found at
moderate hepatic impairment. With severe hepatic impairment (creatinine clearance <70ml/min) a 50%
reduction of the daily maintenance dose is recommended, as the creatinine clearance may underestimate the www.yellowcard.gov.uk and adverse events should also be
renal insufficiency. Contraindications, Warnings etc.: Contraindications: Hypersensitivity to levetiracetam, reported to UCB Pharma Ltd.
other pyrrolidone derivatives or excipients. Precautions: If discontinuing treatment reduce dose gradually as
advised in SPC. Due to its excipients, the oral solution may cause allergic reactions (possibly delayed).
Prescribing physicians are recommended to advise patients to immediately report any symptoms of depression © 2007 UCB Pharma Ltd.
and/or suicidal ideation. Infusion: Keppra concentrate contains 7.196 mg of sodium per vial. To be taken into ® Keppra is a registered trade mark of UCB Pharma Ltd.
consideration by patients on a controlled sodium diet. Interactions: Keppra did not affect serum concentrations Printed in the UK
of phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin or primidone. Drugs Date of preparation: November 2007.
excreted by active tubular secretion could reduce the renal clearance of the metabolite. Levetiracetam 07KP0518a
KEPP7032 ADV CNR.indd 1 19/12/07 16:54:39

Review Article
The Neurological Sleep Clinic – Part 2

Insomnia and parasomnias
V
irtually everyone has experienced short-term intimately involved in central clock mechanisms.
insomnia from time to time, usually in the context Some authorities are enthusiastic about the use of
of some stressor or the anticipation of an exciting diaries or wrist actigraphy in the assessment of insomnia.
event. However, chronic insomnia is also very common, Although the former may give valuable insight into an
affecting up to 10% of the population. It is rather blandly individual’s habits, some of which may be maladaptive,
defined as the perception of inadequate or insufficient the latter is only rarely helpful in documenting the sever-
sleep for a period of three weeks or more, with most ity of insomnia. Since it is only a surrogate measure of
insomniacs having a history that dates back for many actual sleep, if a subject remains completely still although
years. Most commonly, the problem is one of both sleep awake, misleading information may be obtained. Dr Paul Reading, MA, FRCP, PhD,
onset and subsequent sleep maintenance although some A number of neurological conditions, both common is a consultant neurologist based at
have only one or other of these elements. In typical chron- and rare, may have insomnia as a prominent disabling the James Cook University
ic or so-called ‘psycho-physiological insomnia’, a trigger or symptom, assuming it is picked up from the history. Hospital, Middlesbrough. He has
trained in Cambridge, Edinburgh
adverse life event can usually be identified at the start of Somnolent parkinsonian patients frequently have frag- and Newcastle. Over the last seven
symptoms. Subsequent insomnia and concerns over poor mented overnight sleep with early wakening as key ele- years he has developed an academ-
sleep seem to fuel further symptoms although it is usual- ments of their disturbed sleep-wake cycle. This presum- ic and clinical interest in sleep
ly presumed there is also some ill defined constitutional ably directly reflects brainstem pathology although drugs medicine and been secretary of the
British Sleep Society for four years.
predisposition or central ‘wiring problem’ combined with and mood disorder may be additional factors. The ulti- Narcolepsy and the sleep disorders
varying degrees of maladaptive habits developed by the mate rare neurodegenerative cause of insomnia, namely associated with neurodegenerative
sufferer. Examples of the latter include frequent checking fatal familial insomnia, probably reflects the result or rel- disease are particular areas of
of the clock through the night or using the bedroom for atively specific thalamic dysfunction caused by prion pro- interest.
activities other than sleep. Although psychological or even tein accumulation.
psychiatric factors are clearly important in most forms of Several rare autoimmune or paraneoplastic syndromes Correspondence to:
insomnia, additional elements of more interest to neurol- such as limbic encephalitis may also produce severe Dr Paul Reading,
ogists are often relevant as will be discussed. insomnia with or without hallucinatory intrusions as part Department of Neurology,
The James Cook University
Parasomnias, literally ‘events during sleep’, can almost of the clinical spectrum. Indeed, a good sleep history is Hospital,
be considered normal in children. However, abnormal often a useful diagnostic marker in such conditions. Middlesbrough, TS4 3BW, UK.
behaviours arising from sleep, invariably with reduced Email. Paul.Reading@stees.nhs.uk
awareness, are not uncommon in adults, usually in those Parasomnias
with a childhood background of sleep-walking. It can be Parasomnias are usually classified according to the sleep
important to diagnose these sleep-related phenomena stage from which they arise and are broadly divided into
confidently from history alone, especially since tests are REM and non-REM types. The latter are extremely com-
rarely helpful. A mis-diagnosis of nocturnal epilepsy is mon in children and form a spectrum of night terrors,
not rare and can lead to unnecessary treatment and confusional arousals and actual sleepwalking. Events
restrictions. occur when a subject arouses abnormally and incomplete-
ly from deep non-REM sleep usually within 90 minutes of
Insomnia sleep onset. It is not uncommon for such phenomena to
At best, the majority of UK sleep centres deal with insom- persist into adulthood in which case their nature may
niacs poorly. At worst, they refuse even to see them. This is change. Complex behaviours such as cooking or even
mostly because the best recognised treatment for primary driving are well described and violent parasomnias are Figure 1: Algorithm for assessing
insomnia, certainly that occurring at sleep onset, is cogni- increasingly seen in medico-legal contexts. If parasomnias subjects with insomnia.
RLS – restless legs syndrome;
tive behaviour therapy for which it is extremely difficult to start to occur in adults with a distant childhood history of OSA – obstructive sleep apnoea
find interested practitioners with expertise, at least in the
NHS. However, not infrequently, secondary causes of
insomnia can be recognised and successfully treated with
relative ease. An algorithm is shown in Figure 1.
If symptoms are not volunteered, RLS can be missed as
a relatively common and treatable trigger for sleep onset
insomnia or, indeed, poor sleep maintenance. Associated
periodic limb movements during sleep may also be worth
treating even if the diagnosis is not expected from a bed
partner’s history and movements are subsequently picked
up with overnight recording. In addition, it can be appro-
priate to address pain or discomfort arising from muscu-
loskeletal disorders including fibromyalgia and other gen-
eral medical conditions such as reflex oesophagitis which
can act as a significant ‘hypnotoxin’.
Another category of sleep disorder that merits address-
ing as an explanation for some forms of insomnia is
delayed sleep phase syndrome (DSPS), especially in young
populations. In this under-recognised phenomenon, a sub-
ject’s internal ‘clock’ appears to run a few hours behind the
average, making it difficult to settle before 2am and very
difficult to wake up before, say, 10am. This latter feature is
very unusual in simple chronic insomnia. The genetics of
DSPS are an active area of research and many such subjects
may have specific polymorphisms or mutations of genes

Review Article
Table 1: A summary of some key differences between non-rapid eye movement (non-REM) parasomnias and nocturnal seen in REM sleep is diagnostic and is present
epilepsy. even in the absence of frank movements. Long
term treatment with clonazepam is usually suc-
cessful with melatonin gaining a reputation as a
useful second line agent.
Conclusion
In summary, as one commentator famously
noted: “sleep is by the brain and for the brain”.
Although many fundamental questions about
sleep remain unanswered, it is crucial for nor-
mal brain function and, indeed, mental health.
With a broad knowledge of what can go wrong
with sleep, both in normal subjects and those
with neurological problems, a confident diag-
nosis to explain sleep-related symptoms can
similar phenomena, it is always worth consider- nias arising from sleep in the context of REM usually be made without recourse to sophisti-
ing whether another sleep disorder such as sleep behaviour disorder are not uncommon. cated tests. Investigations and, more important-
sleep apnoea is present and acting as a trigger, Most subjects are elderly males, often with a ly, their proper interpretation, have an impor-
potentially fuelling partial arousals from deep parkinsonian syndrome already present or in tant role, however, and it is strongly hoped that
sleep. It is fairly common for parasomnias to be sub-clinical evolution. Injuries, especially to neurologists will have an increasing profile in
confused with nocturnal epilepsy although a bed partners, may be significant and more than sleep medicine, a discipline that deserves and
good history usually suffices for a confident justify long term treatment. The diagnosis is needs their attention.
diagnosis. Some key pointers for distinguishing usually clear from history alone. Typically the
the two entities are given in Table 1. subject lashes out in deep sleep with brief upper
Occasionally, there is considerable doubt as limb movements and vocalisations. The eyes Key references for further reading
to the nature of abnormal nocturnal behav- are usually closed and complex behaviours American Academy of Sleep Medicine. The International
iours and investigations may be considered. including mobilisation are rare. Dream recall is Classification of Sleep Disorders, 2nd Edition. AASM.
Unfortunately, it is relatively rare to capture the norm and subjects usually describe defen- Rochester 2005.
non-REM parasomnias with overnight moni- sive manoeuvres as an explanation for the vio- Espie C. Overcoming Insomnia and Sleep Problems.
toring and recording between events is general- lent behaviour. Since REM sleep occurs at inter- London: Constable and Robinson, 2006.
ly normal or non-specific. Providing a patient vals through the night, events may also recur Morin C, Hauri PJ, Espie C, et al. Non-pharmacologic treat-
ment of chronic insomnia. An American Academy of Sleep
with video equipment for home monitoring with a particularly high incidence at around Medicine review. Sleep 1999;22:1134-56.
may be cost effective. 4am. If overnight polysomnography is per- Reading PJ. Parasomnias: the spectrum of things that go
In a neurological setting, violent parasom- formed, the loss of the normal muscle atonia bump in the night. Pract Neurol 2007;7:6-15.
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Prevention and Treatment of Vasospasm following Subarachnoid Possible New Treatments in Muscular Dystrophy
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British Neurologists and the Founding of an Elite Medical Society


Review Article
Magnetic Resonance Imaging in Multiple Sclerosis –

A Brief Review
MS pathology intravenously are taken up by phagocytic monocytes and Dr Declan Chard is a Clinical
Our concept of pathology in multiple sclerosis (MS) has macrophages, tagging them even after they have entered Research Associate at the Institute
of Neurology, University College
recently evolved from one of relatively focal white matter the CNS;7 and antibody-conjugated micro particles of London. He has research interests
(WM) inflammatory demyelination, to one of a more iron oxide can target specific CNS molecules, with a in multiple sclerosis and a variety
global process affecting the whole central nervous system recently developed vascular cell adhesion molecule mark- of magnetic resonance imaging
(CNS), both WM and grey matter (GM), with spatially er hinting at the potential value of such labels in MS.8 techniques.
variable inflammation, demyelination and remyelination, However, use of MR contrast media is not without poten- Professor David Miller is Professor
glial proliferation, and neurodegeneration.1,2,3 It has also tial risk; nephrogenic systemic fibrosis has been described of Clinical Neurology at the
become clear that focal WM lesions explain only a frac- in people who have received gadolinium based contrast Institute of Neurology, University
tion of the disability accrued by patients; changes in agents, and this has led to a re-evaluation of its use, par- College London and Honorary
Consultant Neurologist at the
regions not overtly abnormal on conventional magnetic ticularly in people with pre-existing renal impairment.9 National Hospital for Neurology
resonance imaging (MRI) scans contribute at least as and Neurosurgery. His major clini-
much to clinical outcomes.4 Indeed, it is thought that Quantitative magnetic resonance imaging cal and research interests are multi-
widespread neurodegeneration, which seems to be only MRI is moving from a paradigm of photography to one of ple sclerosis and magnetic reso-
nance imaging. He is Head of the
partly related to focal WM inflammation, is a key factor cartography, requiring ever more technically demanding Department of Neuroinflammation
determining long term clinical outcomes in MS. acquisition and processing protocols that, at present, limit and is a joint leader of the Multiple
the use of many quantitative MRI measures to research Sclerosis/NMR Research Unit at the
Conventional magnetic resonance imaging projects rather than routine practice; perhaps those near- Institute of Neurology. Supported
by the MS Society of Great Britain
Conventional structural MRI is readily able to detect focal est to application in the clinic are measures of brain atro- and Northern Ireland, this research
WM lesions, but is not so good for spotting GM lesions or phy. Brain atrophy is thought to reflect neuronal and group has been using MR imaging
diffuse changes. WM lesions may been seen on both T2 axonal loss, and as such has been of particular research and spectroscopy to improve the
(as hyper-intensities) and T1 (as hypo-intensities) weight- interest recently. Measurement of brain atrophy relies on accuracy of diagnosis of MS, identi-
fy MR measures to predict the
ed images, with more lesions usually seen on the T2- high quality structural images, with sufficient contrast to future course, improve understand-
weighted scans. This mismatch between lesion visibility reasonably define tissues. Broadly, methods can be divid- ing of the mechanisms of disability
on T2 and T1 weighted images is thought to reflect differ- ed into registration or segmentation-based measures, and recovery, and monitor new
ences in pathological specificity; persistent lesion hypo- although most combine elements of both. Registration- treatments. He is Co-Chief Editor
of the Journal of Neurology.
intensity on T1 images seems to correlate with axonal loss, driven approaches seek to determine how much a region
while T2 hyper-intensity is pathologically non-specific.5 defined on one scan has to be stretched or crushed to fit
The differentiation of acute inflammatory from non- an equivalent region on another scan; when applied to Correspondence to:
inflammatory lesions is aided by contrast-enhancing MRI serially acquired MRI data, differences between scans Dr Declan Chard
NMR Research Unit,
scans with gadolinium chelates; these agents non-specifi- approximate the degree of atrophy; when applied to sin- Department of
cally mark regions where the blood brain barrier is com- gle scans registered to a reference image, estimates of rel- Neuroinflammation,
promised through a variety of processes, including ative volume differences, i.e. normalisation factors, are Institute of Neurology,
inflammation.6 Iron based contrast agents have the poten- obtained. Segmentation-powered techniques seek to University College London,
London, UK.
tial to illuminate different aspects of inflammatory activi- deliver absolute measures of tissue volumes, but results T. +44 (0)20 7829 8771,
ty in the CNS: ultra-small particles of iron oxide given are often presented as ratios to concurrently determined F. +44 (0)20 7278 5616,
Email. d.chard@ion.ucl.ac.uk
Table 1: Main currently available MRI techniques and their routine clinical applications in MS Acknowledgements
We thank Valerie Anderson – NMR
MRI modality Main pathological substrate and localisation of abnormalities in MS Clinical Application Research Unit, Department of
Neuroinflammation, Institute of
Neurology, University College
T1 and T2 weighted Visualises mostly white matter lesions. Not pathologically specific, Core element of the current McDonald
London, London, UK – for provid-
structural imaging but T1 hypo-intensity appears correlate better than T2 hyper-intensity MS diagnostic criteria, and monitoring ing the image shown in Figure 1.
with axonal damage. disease course.
Gadolinum chelates Localised non-vascular enhancement represents disruption of the Core element of the McDonald MS
contrast imaging blood brain barrier; in MS this is associated with active inflammation, diagnostic criteria, and monitoring
mostly seen in white matter lesions. disease course.
Volumetric imaging Brain and cord atrophy represents a combination of cellular atrophy Not routinely used.
and loss, and appears to mirror irreversible neuronal loss. Atrophy
has been observed in both grey and white matter.
Diffusion tensor Assesses tissue, in particular tract, integrity; it is usually abnormal Not routinely used in MS, but
imaging in white matter lesions, but may also be subtly abnormal in increasingly used to determine
normal appearing tissues. the age of vascular lesions.
Magnetisation transfer Assesses tissue myelination; it is usually abnormal in white matter Not routinely used.
imaging lesions, but may also be subtly abnormal in normal appearing tissues.
Spectroscopy Provides relatively cell specific measures of neuronal damage Not routinely used.
(as represented by concentrations of N-acetyl-aspartate) and glial
activation or proliferation (as represented by concentrations of
myo-inositol). Reductions in N-acetyl-asparate concentrations have
been detected in grey and white matter, and lesions; increases in
myo-inositol have been seen in normal appearing and lesional
white matter.

Review Article
Table 2: McDonald criteria (2005) for establishing a diagnosis of MS.
Relapse onset MS, after a single clinical event and with initial signs of one focal abnormality in the CNS, so requiring further evidence of both dissemination in space and time.
Dissemination in space Dissemination in time
If unmatched CSF oligoclonal bands are not detected, or have not been tested for, Any of the following on MRI:
at least three out of the following:
• Compared with a reference T2-weighted scan undertaken at least 30
• One or more gadolinium enhancing lesions in the brain or spinal cord; days after the onset of the index clinical episode, any new lesions
• If no gadolinium enhancing lesions are seen, then nine or more brain and or seen on any subsequent T2-weighted scans;
spinal cord lesions visible on T2-weighted scans;
• Three or more months after the initial clinical event, any gadolinium
• One or more infratentorial or spinal cord lesions;
enhancing lesion observed in any CNS region to which the original
• One or more juxtacortical lesions;
symptoms and signs cannot be attributed;
• Three or more periventricular lesions;
Or Or
• Objective clinical evidence consistent with at least one further focal CNS lesion. • A further clinical event, lasting at least 24 hours, consistent with the
If unmatched CSF oligoclonal bands are detected: diagnosis.
• Two or more MRI visible lesions consistent with the diagnosis.
Or
• Objective clinical evidence consistent with at least one further focal CNS lesion.
Primary progressive MS, after at least one year of clinical disease progression as determined retrospectively or prospectively.
Two of the following:

• If visual evoked potentials are normal, or have not been tested, nine or more brain lesions visible on T2-weighted images;
• If visual evoked potentials are abnormal and consistent with demyelination, four or more brain lesion visible on T2-weighted images;
• Two or more focal spinal cord lesions visible on T2-weighted images;
• Unmatched oligoclonal bands detected in the CSF.
The criteria assume that no viable alternative explanation for a person’s symptoms and signs has been found after appropriate investigation.
intracranial volumes; this adjustment yields

measures which are naturally less variable
between people, and which are less susceptible
to scanner calibration drift, which can be a
problem with serial MRI studies. GM specific
measures may be of added value in MS, offering
better surrogate markers of disease progression
compared with WM or whole brain parame-
ters.10 In clinical trials of potential neuroprotec-
tive agents, the inclusion of MRI brain atrophy
measures may reduce both the number of par-
ticipants and the follow-up period required to
show a significant treatment effect, when com-
pared with studies relying purely on clinical
outcome measures.11
As presently acquired, conventional struc-
tural MRI is designed to maximise spatial
clarity but not to serve as an objective quan-
tifiable measure of a tissue’s intrinsic charac-
teristics; however a suite of newer MRI tech-
niques are able to provide such information.
Magnetisation transfer (MT) imaging offers
insight into myelination,12 estimating the pro-
portion of membrane associated macromole-
cular protons (not readily seen with conven-
tional MRI) in a region; abnormalities in MT
have been detected in both lesional and non-
lesional tissues in MS, and such measures Figure 1: Brain volume loss in MS demonstrated using the ‘Structural Image Evaluation, using Normalisation, of Atrophy’
technique applied to two MRI scans acquired one year apart. A coronal brain slice is presented, rendered with a colour
have been recommended for use in studies of overlay, where blue indicates volume loss and red indicates gain. For further details see Anderson et al.10 Image courtesy of
treatments aimed at promoting remyelina- Valerie Anderson.
tion.13 Diffusion tensor imaging yields a meas-
ure of tissue integrity, with changes again seen
in both MS lesional and non-lesional tissues,14 health and density, and has been found to be ation times, and tissue perfusion, although
and has demonstrated potential in the assess- reduced early in the clinical course of MS, in these measures have been less extensively
ment of MS associated WM tract damage.15 WM and GM; myo-inositol, which is prefer- employed in MS, compared with those men-
Proton spectroscopy allows the estimation of entially concentrated in glia, has been found tioned previously.
brain chemical concentrations: N-acetyl- to be elevated in lesions and normal-appear- The functional impact of MS is also being
aspartate, which is found almost exclusively in ing WM, suggesting glial activation and or addressed with MRI, beyond that of simply
neurons and their axonal projections in the proliferation.16 Using MRI, it is also possible associating measures of tissue damage with clin-
adult brain, offers a measure of neuronal to quantitatively measure T1 and T2 relax- ical outcomes; recent functional MRI studies

Review Article
suggest that cortical plasticity may attenuate the effects of focal damage in References
MS, and promote recovery beyond that achievable through localised 1. Dhib-Jalbut S. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis.
Neurology. 2007 May 29;68(22 Suppl 3):S13-21.
innate tissue repair mechanisms alone (for example 17).
2. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis.
Neurology. 2007 May 29;68(22 Suppl 3):S22-31.
McDonald diagnostic criteria and other clinical applications 3. Miller RH, Mi S. Dissecting demyelination. Nat Neurosci. 2007 Nov;10(11):1351-4.
Technical limitations and the complex data processing required to 4. Neema M, Stankiewicz J, Arora A, Guss ZD, Bakshi R. MRI in multiple sclerosis: what's
derive quantitative MR measures have meant that routine clinical inside the toolbox? Neurotherapeutics. 2007 Oct;4(4):602-17.
application of MRI has focused mainly on identifying lesions to sup- 5. van Walderveen MA, Kamphorst W, Scheltens P, van Waesberghe JH, Ravid R, Valk J,
Polman CH, Barkhof F. Histopathologic correlate of hypointense lesions on T1-weighted
port the diagnosis of MS, and excluding or confirming alternative diag- spin-echo MRI in multiple sclerosis. Neurology. 1998 May;50(5):1282-8.
noses. MRI on it own cannot be used to establish a diagnosis of MS, 6. Essig M, Weber MA, von Tengg-Kobligk H, Knopp MV, Yuh WT, Giesel FL. Contrast-
but can provide key evidence for evolving multifocal pathology. The enhanced magnetic resonance imaging of central nervous system tumors: agents, mecha-
latest diagnostic guidelines in MS, the revised McDonald criteria,18 nisms, and applications. Top Magn Reson Imaging. 2006 Apr;17(2):89-106.
allow the diagnosis of MS after a single clinical event, where there are 7. Petry KG, Boiziau C, Dousset V, Brochet B. Magnetic resonance imaging of human brain
macrophage infiltration. Neurotherapeutics. 2007 Jul;4(3):434-42.
sufficient MRI visible brain and cord lesions, and lesion accrual is
8. McAteer MA, Sibson NR, von Zur Muhlen C, Schneider JE, Lowe AS, Warrick N,
demonstrated on scanning undertaken after the index clinical event. A Channon KM, Anthony DC, Choudhury RP. In vivo magnetic resonance imaging of acute
very recent study suggests that in people who have had no episodes brain inflammation using microparticles of iron oxide. Nat Med. 2007 Oct;13(10):1253-8.
suggestive of CNS demyelinaton, the incidental detection on MRI of 9. Penfield JG, Reilly RF Jr. What nephrologists need to know about gadolinium. Nat Clin
MS-like lesions is associated with a relatively high risk of a person hav- Pract Nephrol. 2007 Dec;3(12):654-68.
ing a clinical event consistent with MS within five years.19 However, 10. Anderson VM, Fox NC, Miller DH. Magnetic resonance imaging measures of brain atrophy
in multiple sclerosis. J Magn Reson Imaging. 2006 May;23(5):605-18.
while lesions do appear to predict onset of MS, they are not so good at
11. Kapoor R. Neuroprotection in multiple sclerosis: therapeutic strategies and clinical trial
predicting subsequent disability, even in the longer term, i.e. they mark design. Curr Opin Neurol. 2006 Jun;19(3):255-9.
the process better than its effects.20 While MRI has established itself in 12. Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization transfer ratio
a diagnostic role in MS, it is only just beginning to find a clear place in and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004 Sep;56(3):407-15.
treatment decisions; lesion activity measures form part of the National 13. Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging of the brain,
Institute for Clinical Excellence (2007) recommended criteria for the spinal cord, and optic nerve. Neurotherapeutics. 2007 Jul;4(3):401-13.
14. Pagani E, Bammer R, Horsfield MA, Rovaris M, Gass A, Ciccarelli O, Filippi M. Diffusion
prescription of natalizumab in rapidly evolving severe relapsing-remit-
MR imaging in multiple sclerosis: technical aspects and challenges. AJNR Am J
ting MS. Neuroradiol. 2007 Mar;28(3):411-20.
15. Ciccarelli O, Toosy AT, Hickman SJ, Parker GJ, Wheeler-Kingshott CA, Miller DH,
Where next? Thompson AJ. Optic radiation changes after optic neuritis detected by tractography-based
MRI has already made invaluable contributions to our understanding of group mapping. Hum Brain Mapp. 2005 Jul;25(3):308-16.
MS. In the short term, it remains for quantitative MRI measures to 16. De Stefano N, Filippi M, Miller D, Pouwels PJ, Rovira A, Gass A, Enzinger C, Matthews
PM, Arnold DL. Guidelines for using proton MR spectroscopy in multicenter clinical MS
realise their potential in clinical practice: such measures may help make studies. Neurology. 2007 Nov 13;69(20):1942-52.
the diagnostic criteria even more sensitive and specific; may yield more 17. Forn C, Barros-Loscertales A, Escudero J, Belloch V, Campos S, Parcet MA, Avila C.
reliable prognostic indicators; and provide timely and effective surro- Cortical reorganization during PASAT task in MS patients with preserved working memory
gates of pathological progression, in a way that can usefully inform functions. Neuroimage. 2006 Jun;31(2):686-91.
treatment decisions, preferably before such progression becomes clini- 18. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz
LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker
cally manifest. In the long term, it may be possible to deliver truly cell BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald
and process-specific information from MRI, and integrate such meas- Criteria”. Ann Neurol. 2005 Dec;58(6):840-6.
ures with immunological and genetic data to better characterise the dis- 19. Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P,
ease’s genesis and evolution. From this it is to be hoped that we can Brassat D, Labauge P, Roullet E; CFSEP. Unexpected multiple sclerosis: follow-up of 30
patients with magnetic resonance imaging and clinical conversion profile. J Neurol
develop a range of more effective disease specific treatments, optimise Neurosurg Psychiatry. 2008 Feb;79(2):195-8.
their use on a person-by-person basis, and observe their effectiveness 20. Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, Benton CE, Lanyon R, Thompson AJ,
dynamically with a view to eliminating, or at least markedly curtailing, Miller DH. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse
the clinically apparent effects of MS. onset of multiple sclerosis. Brain. 2008 Jan 29.
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Today, unnecessary seizures restrict 69,000 lives1
The chance to control seizures, not lives
ABBREVIATED PRESCRIBING INFORMATION been reported. Kidney stones have occurred. Use with caution in anemia, leucocytosis, leucopenia, lymphadenopathy, pancytopenia,
Zonegran® (zonisamide) patients with risk factors for nephrolithiasis, including prior stone thrombocytopenia, metabolic acidosis, hallucination, insomnia,
Please refer to the SmPC before prescribing. formation, a family history of nephrolithiasis and hypercalcuria. Use amnesia, coma, grand mal seizure, myasthenic syndrome, neuroleptic
Presentation: Hard capsules containing 25 mg, 50 mg or 100 mg with caution in patients treated with carbonic anhydrase inhibitors, malignant syndrome, dyspnoea, pneumonia aspiration, respiratory
zonisamide. Indication: Adjunctive therapy in the treatment of adult e.g. topiramate. Decreased sweating, elevated body temperature and disorder, pancreatitis, hepatocellular damage, anhidrosis, erythema
patients with partial seizures, with or without secondary generalisation. heat stroke have been reported. Patients should maintain hydration multiforme, pruritis, Stevens-Johnson syndrome, rhabdomyolysis,
Dose and administration: Adult: Zonegran must be added to existing and avoid excessive temperatures. Monitor pancreatic lipase and hydronephrosis, renal insufficiency, urine abnormality, blood creatine
therapy. Initial daily dose is 50 mg in two divided doses. After one week, amylase levels and consider discontinuation in patients with signs and phosphokinase increased, blood urea increased, liver function tests
increase to 100 mg daily and then at one weekly intervals, in 100 mg symptoms of pancreatitis. In cases of severe muscle pain/weakness with abnormal, heat stroke. Legal Category: POM Presentation: PVC/
increment. Consider two weekly intervals in renal or hepatic impairment or without fever, assess markers of muscle damage, e.g. serum creatine PCTFE/aluminium blisters. Basic UK NHS cost: Zonegran 25 mg:
and patients not receiving CYP3A4-inducing agents. Zonegran can be phosphokinase and aldolase levels, and consider discontinuation. packs of 14 £8.82, Zonegran 50 mg: packs of 56 £47.04, Zonegran 100
administered once or twice daily after the titration phase. Withdraw Zonegran 100 mg hard capsules contain E110, which may cause allergic mg: packs of 56 £62.72. Basic Irish cost: Zonegran 25 mg: packs of
gradually. Elderly and patients with renal or hepatic impairment: reactions. Caution in patients less than 40 kg. In patients with weight loss 14 €12.88, Zonegran 50 mg: packs of 56 €68.32, Zonegran 100 mg:
Caution (see SmPC). Not recommended in severe hepatic impairment. consider dietary supplement, increased food intake or discontinuation. packs of 56 €91.28. Marketing authorisation numbers: Zonegran
Children and adolescents under 18 years: Not recommended. Drug Interactions: No clinically relevant pharmacokinetic effects 25 mg 14 capsules: EU/1/04/307/001, Zonegran 50 mg 56 capsules:
Contra-Indications: Hypersensitivity to zonisamide, sulphonamide on carbamazepine, lamotrigine, phenytoin, sodium valproate, oral EU/1/04/307/003, Zonegran 100 mg 56 capsules: EU/1/04/307/004.
or any excipient. Pregnancy: Zonegran must not be used during contraceptives (ethinylestradiol or norethisterone). Insufficient data Marketing authorisation holder: Eisai Ltd. Further Information
pregnancy unless benefit justifies the risk, in the opinion of the with carbonic anhydrase inhibitors, e.g. topiramate. Zonegran was from/Marketed by: Eisai Ltd, Hammersmith International Centre,
physician. Specialist advice should be given to women who are likely not affected by lamotrigine or CYP3A4 inhibitors. Caution with drugs 3 Shortlands, London,W6 8EE. Date of preparation: November 2007
to become pregnant in order to consider the optimal treatment during inducing urolithiasis, CYP3A4, N-acetyltransferase, glucuronic acid,
pregnancy. Women of childbearing potential must use contraception or drugs which are P-gp substrates. Side effects: The most common Information about adverse event reporting can be found at
during treatment and for one month after discontinuation. Lactation: adverse reactions in controlled adjunctive therapy studies were www.yellowcard.gov.uk Adverse events should also be reported to
Zonisamide is excreted into breast milk. A decision must be made to somnolence, dizziness and anorexia. Adverse reactions associated Eisai Ltd on 0208 600 1400 or Lmedinfo@eisai.net
either discontinue Zonegran or stop breast-feeding. Breast-feeding with Zonegran in clinical studies and post marketing surveillance:Very
should not be resumed until one month after stopping Zonegran. common effects (>1/10): anorexia, agitation, irritability, confusional Reference
Warnings and Precautions: Serious rashes occur in association state, depression, ataxia, dizziness, memory impairment, somnolence, 1. All Party Parliamentary Group on Epilepsy. The human and economic
with Zonegran therapy, including cases of Stevens Johnson syndrome. diplopia. Common effects (>1/100, <1/10): hypersensitivity, disturbance cost of epilepsy in England. Published 27th June 2007.
Zonegran contains a sulphonamide group. Serious immune based in attention, speech disorder, abdominal pain, diarrhoea, nausea, rash,
adverse reactions are associated with the sulphonamide group, e.g. rash, pyrexia, weight decreased. Uncommon (>1/1000, <1/100): pneumonia, Date of preparation: January 2008. Z1119 01/08
allergic reaction, major haematological disturbances including aplastic urinary tract infection, hypokalemia, psychotic disorder, anger,
anaemia. Closely supervise and consider discontinuation in patients aggression, suicidal ideation, suicidal attempt, convulsion, vomiting, Advancing
with unexplained rash. Cases of agranulocytosis, thrombocytopenia, cholecystitis, cholelithiasis, calculus urinary, nephrolithiasis. Very Epilepsy
leukopenia, aplastic anaemia, pancytopenia and leucocytosis have Rare (<1/10,000 including isolated reports): agranulocytosis, aplastic Management
Rehabilitation Article
The Ethical Challenge Posed by Acquired Brain Injury
P
erhaps our first thoughts on seeing the • The limits of ‘duty of care’. Is the fact that
phrases ‘acquired brain injury’ and ‘ethi- Joanna Collicutt McGrath is there are many people who do not have iden-
lecturer in psychology of reli-
cal challenge’ in close proximity to each gion at Heythrop College.
tified acquired brain injury at liberty in the
other, are the extremely difficult and controver- London University. She was community who are a risk to themselves and
sial decisions about the end of life for people head of clinical neuropsycholo- others because of poor social, emotional, and
who are deemed to be in a persistent vegetative gy at Rivermead Rehabilitation behavioural control relevant, or not?
Centre, Oxford, from 1990-
state (PVS). These centre on questions of sen- 2002. Her main areas of interest
• The role of carers in advancing the agendas
tience; the nature and value of human life; are in the psychological and of very physically dependent people where
human dignity and quality of life; the inferred spiritual impact of brain injury, and cognitive therapeu- these agendas are not congruent with their
wishes of the affected person pre-injury; the tic approaches. She is also an Anglican priest. own value system. Should carers ever act
interests of their loved ones; and the interests of Correspondence to: exclusively as ‘objects’ under the direction of
Joanna Collicut McGrath, Heythrop College,
society at large. the affected person?
University of London, Kensington Square,
But PVS is an extreme case, and what is less London, W8 5HQ, UK. • Unpredictability of treatment gains and very
widely recognised is the significant and com- T. +44 (0)20 7795 4264, F. +44 (0)20 7795 4200. large inter-individual variation makes fair
pelling challenge posed by the more common allocation of resources particularly challeng-
kind of severe brain injury that spares the that arise during the process.6 The basic activi- ing. For instance individualised treatment
patient’s sentience, but may devastate her ability ties and attitudes required are: programmes have a tenuous link to evidence
to move, feel, think, remember, communicate, • Sensitivity to and respect for the affected bases, which are limited, and often consist of
and make meaningful relationships. The situa- person’s physical and psychological bound- large group studies of homogenous treat-
tions faced by these people, their families, and aries ment programmes
those who care for them are replete with moral • Taking seriously issues related to their per- • The special needs of children – including
overtones which make themselves felt as ethical sonal appearance protection and appropriate autonomy
dilemmas. These are complex problem situa- • Treating their impairments • Interdisciplinary conflict due to diverging
tions that involve tension and paradox, where all • Optimising their agency and liberty professional and personal values – moral
potential solutions appear to be unfavourable, • Training in meaningful activities and epistemological
where potential solutions conflict, and where it • Supporting them in the resumption of val- • Psychological versus physical risk – is physi-
is difficult to act.1 It is thus not surprising that ued roles and relationships cal safety to be pursued at all costs, including
they evoke strong feelings and conflict both • Helping them to integrate the experience personal despair?
within and between the individual stakeholders. into a meaningful personal narrative Ethical dilemmas relating to these issues are by
The treatment and rehabilitation of people • Managing any associated physical and psy- their nature rarely resolvable to the satisfaction
with acquired brain injury is a potent and dis- chological conditions of all those involved. Nevertheless, a systematic
tinctive source of ethical dilemmas because it The crunch comes in optimising liberty and approach that makes the issues explicit and
involves profound novelty, great complexity, agency. There is little doubt that brain injury gives them due consideration is a highly desir-
only partial information, and a coming togeth- robs individuals of agency through its direct able component of clinical practice in this area.
er of several different value systems and effects, and of liberty through the actions of The psychological impact of engaging with
assumptive worlds.2,3 While some of the ethical others who admit them to hospitals or care these issues, especially if the process has
issues that arise in the context of acquired brain homes, terminate their employment, and so on. involved significant conflict, should also be
injury also arise in the context of other dis- There seems little doubt that some sort of rein- recognised and managed for patient, family,
abling neurological conditions, such as spinal statement of agency and liberty should be the and clinical staff. Good decisions and the man-
cord injury, multiple sclerosis, or the demen- aim of good patient-centred practice. But here agement of the process of ethical decision mak-
tias, there is a unique combination of factors the ethical dilemmas start to emerge: whose ing and action is likely to be helpfully informed
that applies to acquired brain injury. These fac- agency and liberty are we talking about? by individuals with expertise in the areas of
tors have specific psychosocial consequences, Is it the pre-injury person – now idealised moral philosophy and psychology, philosophy
and raise specific ethical issues: and set in stone in family photos, videos, or of mind, religion and spirituality, and law. All
• The onset of the condition is sudden in pre- advance directives? Is it the profoundly changed these may add enlightening perspectives (but
viously healthy individuals person of the present? Is it some, again ide- not answers!) and contribute to the develop-
• Physical, cognitive, emotional, behavioural alised, aspirational person-in-becoming – the ment of wisdom in clinical services and teams.
control systems and their capacity for seam- person who has achieved all his rehabilitation
less functional interaction are all potentially goals? And is it worth tolerating a degree of References
compromised restriction in agency and liberty now for the 1. Sekereka L, Bagozzi R and Jones J. Moral courage in the
• Because of this complexity an unusually later and greater good of increased agency and workplace: Self regulation as the cornerstone of virtuous
action. Abstracts of Second European Conference on
large range of professionals may be involved liberty in the future? And what if optimising the Positive Psychology, 2004;153-4. Arcipelago Edizioni,
• The outcome is uncertain and improve- agency and liberty of the patient has detrimen- Milan.
ments may continue for many years tal effects on other aspects of his wellbeing or 2. Malec J. Ethics in brain injury rehabilitation: existential
• A relatively young population is affected on the agency and liberty of others (other peo- choices among western cultural beliefs. Brain Injury,
1993;7:383-400.
• Life expectancy is often normal ple competing for limited health and social care
3. Tarvydas V and Shaw L. Interdisciplinary team member
The particular combination of sudden and dra- resources, family and friends, clinicians and perceptions of ethical issues in traumatic brain injury
matic cognitive and physical losses, primary other professional carers, the general public)? rehabilitation. NeuroRehabilitation 1996;6:97-111.
emotional processing difficulties, change of My recent book7 includes a series of case stud- 4. Oddy M. He’s no longer the same person: How families
appearance, and the psychological reaction of ies which include the following main issues: adjust to personality change after head injury. In N
Chamberlain, ed. Traumatic brain injury rehabilitation,
the affected person and others result in a • Mental/cognitive capacity and the issue of 1995;167-80. Chapman and Hall, London.
deconstruction of ‘personality’4 and profoundly ‘acquired imprudence’ associated with exec- 5. Jackson H and Manchester D. Towards the development
changed sense of personal identity.5 I have utive impairment – the right to make ‘bad’ of brain injury specialists. Neurorehabilitation
argued that the central task facing the patient, decisions 2001;16:27-40.
family, and clinicians is therefore establishing a • The naturalness and danger of paternalism 6. McGrath J. Beyond restoration to transformation: positive
outcomes in the rehabilitation of acquired brain injury.
new sense of identity continuous with, but not when dealing with people who are learning Clinical Rehabilitation 2004;18:767-75.
stuck in, the past, while managing the medical to walk, talk, be continent, behave in a 7. Collicutt McGrath, J. Ethical practice in brain injury
complications, pain, and emotional distress socially appropriate manner rehabilitation. 2007 Oxford University Press, Oxford.

SWZ3208 297x210 ACNR:SWZ3208 297x210 ACNR 29/2/08 16:48 Page 2
When he needs Parkinson’s disease treatment day and night…
…Neupro delivers1–3
ABBREVIATED PRESCRIBING INFORMATION (e.g. 2 mg/24h in Week 1, 4 mg/24 h in Week 2, patch application to minimise the risk of skin reactions. hallucinations, confusion state, insomnia, abnormal
(Please consult the Summary of Product Characteristics 6 mg/24 h in Week 3 and 8 mg/24 h in Week 4), until In case of generalised skin reaction associated with use dreams, headache, dyskinesia, orthostatic hypotension,
(SmPC) before prescribing.) an effective dose is reached. Maximal dose is 8 mg/24 h. of Neupro®, discontinue treatment. Avoid exposure to vomiting, constipation, diarrhoea, dry mouth, dyspepsia,
NEUPRO® Presentation: Neupro® is a thin, matrix- Adjunctive therapy (with levodopa): treatment initiation is direct sunlight until the skin is healed. If treatment is to hepatic enzyme increase, hyperhydrosis, erythema,
type square transdermal patch. Active Ingredient: at 4 mg/24 h and increased weekly in 2 mg/24 h be withdrawn, it should be gradually reduced to avoid pruritus, asthenic conditions, peripheral oedema,
Rotigotine. 2 mg/24 h transdermal patch is 10 cm2 and increments, up to a maximal dose of 16 mg/24 h. symptoms of neuroleptic malignant syndrome. decreased weight, fall. Consult SmPC in relation to
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disease, either with or without concomitant levodopa Precautions: External heat should not be applied to controlled by rotigotine. Pregnancy and lactation: SCHWARZ PHARMA Ltd, Shannon, Industrial Estate,
therapy. Dosage and Administration: Neupro® is the patch. Dopamine agonists are known to cause Rotigotine should not be used during pregnancy. Co. Clare, Ireland. Further information is
applied to the skin once a day. The patch remains on hypotension, and monitoring of blood pressure is Breast-feeding should be discontinued. Driving etc.: available from: UCB Pharma Ltd, 208 Bath Road,
the skin for 24 hours and will then be replaced by recommended. Where somnolence or sudden sleep Rotigotine may have major influence on the ability to Slough, Berkshire, SL1 3WE. Tel: 01753 534655.
a new one at a different application site. Monotherapy: onset occurs, or where there is persistent, spreading or drive and use machines. Adverse Effects: Very Fax: 01753 536632. Email: medicalinformation@
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2 mg/24 h. Dose increased by 2 mg/24 h each week reduction or termination of therapy. Rotate the site of application site reactions. Common (between 1%-10%): [RAJB-00132a]. Neupro is a registered trademark.
Information about adverse event reporting can be found at www.yellowcard.gov.uk

and adverse events should also be reported to UCB Pharma Ltd.
References: 1: Watts RL et al. Neurology 2007; 68: 272–6. 2: Neupro Summary of Product Characteristics. 3. Giladi N et al. Poster presented at EFNS 2006.
Date of literature preparation: February 2008.
NEU3637 07NE0022g
Neurophysiology Article
Evoked Potentials and the Prognosis of Comatose Patients

Receiving Intensive Care
hilst death is relatively easily identified, its pre- especially when poor prognoses tend to become self fulfill-
W diction on an individual patient basis during

the course of critical illness is more complex. In
a hospital setting, anticipating death allows the carers to
ing, and demonstrates a need for the judicious use and tim-
ing of evoked potential recordings. However, this is true for
clinical observations alone and it seems that the predictive
advise the patient and their loved ones of the prognosis, to value of SSEPs is superior to clinical tests,11 and can be pre-
withdraw futile, burdensome treatment and to implement dictive of a poor outcome even when brainstem function is
end of life care pathways. In comatose patients clinical preserved after anoxia.12 Indeed the American Academy of
observation forms the basis of prognostic predictions but Neurology has endorsed the use of SSEPs (with a level B rat-
is prone to error; for example the widely used Glasgow ing) in a decision algorithm for prognostication of coma- Dr Nick Kane MSc MD (Hons)
Coma Scale (GCS), really a clinical measure of conscious- tose survivors after successful cardiopulmonary resuscita- FRCS is a Consultant Clinical
ness, can be unduly pessimistic.1 A systematic review of tion.13 Perhaps of greater consequence than medication Neurophysiologist in the Grey
1,914 comatose survivors of cardiac arrest found five clin- effects, which can potentially be reversed, is that a multicen- Walter Department at Frenchay
Hospital, Bristol, with an interest in
ical signs which strongly predict death or poor neurolog- tre trial revealed that there was only moderate interobserver the application of evoked potentials
ical outcome: absent corneal reflexes, absent pupillary agreement on the interpretation of evoked potentials.14 in surgery and critical care.
response, absent withdrawal response to pain, no motor Furthermore, although the absence of short latency
response at 24 hours, and no motor response at 72 hours, responses is a poor prognostic feature, their presence does
Correspondence to:
but none which strongly predicted a good neurological not guarantee the return of consciousness or survival, and Nick Kane MSc MD (Hons)
outcome.2 The prediction of good outcomes is perhaps we must look to other electrophysiological probes.15 FRCS,
equally important, particularly in identifying those sur- Long latency event related potentials (ERPs) have been Grey Walter Dept of
vivors of coma who will require intensive neurorehabilita- the subject of several reviews,16,17 and the findings of one Neurophysiology,
Frenchay Hospital,
tion. Over the last 25 years there have been many attempts meta-analysis are now known.18 This analysis pooled data Bristol,
to improve prognostication by adding electrophysiologi- from 10 studies of patients in coma and other low respon- BS16 1LE, UK.
cal and biochemical measures of functional integrity and sive states (GCS <12) of various aetiologies in order to T. +44 (0)117 9701212 ext 3648
neuronal damage, respectively. Is it time then to introduce estimate the predictive power (odds ratio, OR, and its Email. Nick.Kane@nbt. nhs.uk
such measures into routine clinical practice? confidence limits, CI) of several ERPs measures (see
Electrophysiological assessment of the central nervous Table).18 Since the greater the value of the OR (or more
system initially concentrated on the electroencephalogram precisely the lower limit of its CI) indicates that presence
and short latency evoked responses, in particular the of the ERP component is a significant predictor of awak-
somatosensory evoked potential (SSEP), whilst latterly ening, the P300 would seem to be the test of choice.
investigators have evaluated long latency event related Indeed P300 was the original ERP component reported in
potentials (ERPs), such as the P300 and mismatch negativ- four patients who recovered from traumatic coma,19
ity (MMN).3 The assumption is that their detection reflects which was subsequently confirmed in a large cohort.20
functional integrity of cerebral neuronal pathways, which However, MMN is an automatic process in both sleep and
are not accessible to the brainstem-focussed clinical exam- wakefulness whilst P300, in the awake state at least, is
ination, and may therefore provide early indications of the modulated by arousal and attention, which clearly can be
potential for neurological recovery and cognition (see ref- neither controlled nor assessed in an unresponsive
erence 4 for a review). In contrast to the GCS, they are not patient. It was largely this potential confounding factor
measures of consciousness per se and it is important to that encouraged investigators to assess the automatic pre-
emphasise that they provide complementary information attentive MMN auditory novelty detection mechanism,
to clinical observations. It has recently been elegantly and which may account for its apparent greater specifici-
demonstrated by imaging studies, in this and other jour- ty (91% versus 77% for P300).18 The presence of MMN
nals, that there are ‘islands’ of preserved cerebral function has been shown to be predictive of awakening from both
in patients who are unresponsive.5 Electrophysiological acute traumatic and non traumatic coma,3,21,22 and the veg-
probing of these islands may indicate higher levels of etative state.23 Unfortunately its presence has also been
information processing which underpin awareness and seen to falsely predict a favourable outcome (in 16 out of
responsiveness if not consciousness itself, although of 460 patients).18 As with short latency responses we are
course information processing alone is not consciousness uncertain of the interaction of MMN with sedating
as such. What then is the evidence for the clinical applica- agents, and indeed it has been shown to be attenuated by
tion of evoked and event-related potentials? deep sedation with propofol.24 Its absence is uninforma-
We have the benefit of a number of systematic reviews of tive of prognosis.
the significance of bilateral absence of SSEPs in both trau- In conclusion, there is evidence that both evoked and
matic and non-traumatic coma 24 hours after onset.6,7,8 It event related potentials could help refine clinical predic-
appears that the bilateral absence of short latency cortical tions of outcome from coma. It is fair to say that evoked
potentials is very nearly 100% specific for prediction of a potential recordings are reliable predictors of poor outcome
poor outcome (defined as death or persistent vegetative and are inexpensive, non-invasive tests that can be safely
state)6 after hypoxic ischaemic and intracranial haemor- recorded at the patient’s bedside. The neurophysiologist
rhagic insults, but is slightly less predictive after traumatic
brain injury (TBI), particularly in children.7 Indeed after Table of Odds Ratio with Confidence Intervals (CI) for prediction of survival by various
TBI as many as 12 patients out of 777 had favourable out- Event Related Potential (ERP) components from pooled data.
comes (good or moderate disability) despite bilaterally
absent SSEPs.8 This observation has been detailed in a num- ERP component Odds Ratio (OR) 95% CI Patient Number
ber of case reports of patients making good recovery after N100 2.85 1.91-4.27 548
both anoxia and TBI, where barbiturate coma or raised MMN 6.53 3.55-12.01 470
intracranial pressure may have contributed to the loss of P300 8.79 4.88-15.83 313
cortical responses.9,10 Clearly this gives cause for concern,

Neurophysiology Article
needs experience to be aware of certain caveats two recording them on a fairly frequent basis. can be achieved. The inherent false positive rates
in their clinical application, and in spite of being Although in their infancy event-related poten- may of course limit the use of electrophysiologi-
widely available throughout the UK are probably tials have shown some promise in heralding cal predictors of outcome in coma, which is gen-
under-utilised. My own telephone survey of 20 awakening and favourable neurological prog- erally a self-limiting condition.
Clinical Neurophysiology departments across noses, and can therefore complement evoked
England and Wales revealed that all bar one reg- potentials. ERPs are more complex in both their Acknowledgement
With thanks to my colleague Dr Alex Manara, consultant
ularly record EEGs in Intensive Care Units, but recording technique and interpretation, and will anaesthetist, for his extremely helpful comments.
only five ever record evoked potentials, with just require further evaluation before clinical utility
References
1. The Brain Trauma Foundation. Glasgow Coma Scale 10. Theilen HJ, Regaller M, von Kummer R, Pohlmann- 17. Lew HL, Poole JH, Castaneda A, Salerno RM, Gray M.
Score. Journal of Neurotrauma 2000;17:563-71. Eden B, Schckert G, Albrecht MD. Functional recovery Prognostic value of evoked and event-related potentials I
2. Booth CM, Boone RH, Tomlinson G, Detsky AS. Is this despite prolonged bilateral loss of somatosensory evoked moderate to severe brain injury. J Head Trauma Rehabil
patient dead, vegetative, or severely neurologically potentials: report on two patients. JNNP 2000;68:657-60. 2006;21:350-60.
impaired? JAMA 2004;291:870-9. 11. Zanderbergen EGJ, Hijdra A, Koelman JHTM, Hart 18. Daltrozzo J, Wioland N, Mutschler V, Kotchoubey B.
3. Kane NM, Curry SH, Rowlands CA, Manara AR, Lewis AAM, Vos PE, Verbeek MM, de Haan RJ, for the Predicting coma and other low responsive patients out-
T, Moss T, Cummins, Butler SR. Event-related potentials PROPAC Study Group. Prediction of poor outcome with- come using event-related potentials: a meta-analysis. Clin
– neurophysiological tools for predicting emergence and in the first 3 days of postanoxic coma. Neurology Neurophysiol 2007;118:606-14.
early outcome from traumatic coma. Intensive Care Med 2006;66:62-8. 19. Reuter BM, Linke DB. P300 and coma. In Maurer K, ed.
1996;22:39-46. Topographic brain mapping of EEG and evoked poten-
12. Rothstein T. The role of evoked potentials in anoxic-
4. Young GB, Wang JT, Connolly JF. Prognostic determina- tials. New York: Springer-Verlag;1989:192-6.
ischaemic coma and severe brain trauma. J Clin
tion in anoxic-ischaemic and traumatic encephalopathies. Neurophysiol 2000;17:486-97. 20. Guerit JM, Verougstraete D, de Tourtchaninoff M,
J Clin Neurophysiol 2004;21:379-90. Debastisse D, Witdoeckt C. ERPs obtained with the audi-
13. Wijdicks EFM, Hijdra A, Young GB, Bassetti CL, Wiebe tory oddball paradigm in coma and altered states of con-
5. Coleman M, Owen A, Pickard J. Functional imaging and
S. Practice Parameter: Prediction of outcome in comatose sciousness: clinical relationships, prognostic value, and ori-
the vegetative state. ACNR 2007;7:35-6.
survivors of cardiopulmonary resuscitation (an evidence- gin of components. Clin Neurophysiol 1999;110:1260-9.
6. Zanderbergen EGJ, de Haan RJ, Stoutenbeek CP, based review). Neurology 2006;67:203-10.
Koelman JHTM, Hijdra A. Systematic review of early 21. Fischer C, Luauté J, Adeleine P, Morlet D. Predictive
prediction of poor outcome in anoxic-ischaemic coma. 14 Zanderbergen EGJ, Hijdra A, de Hann RJ, van Dijk JG, value of sensory and cognitive evoked potentials for awak-
Lancet 1998;352:1808-12. Ongerboer de Visser BW, Spaans F, Tavy DLJ, Koelman ening from coma. Neurology 2004;63:669-73.
JHTM. Interobserver variation in the interpretation of 22. Naccache L, Puybasset L, Gaillard R, Serve E, Willer J-C.
7. Robinson LR, Micklesen PJ, Tirschwell DL, Lew HL.
SSEPs in anoxic-ischaemic coma. Clin Neurophysiol Auditory mismatch negativity is a good predictor of awak-
Predictive value of somatosensory evoked potentials for
2006;117:1529-35. ening in comatose patients: a fast and reliable procedure.
awakening from coma. Crit Care Med 2003;31:960-7.
15. Logi F, Fischer C, Murri L, Mauguière F. The prognostic Clin Neurophysiol 2005;116:988-90.
8. Carter BG, Butt W. Review of the use of somatosensory
evoked potentials in the prediction of outcome after severe value of evoked responses from primary somatosensory 23. Wijnen VJM, van Boxtel GJM, Eilander HJ, de Gelder B.
brain injury. Crit Care Med 2001;29:178-86. and auditory cortex in comatose patients. Clin Mismatch negativity predicts recovery from the vegetative
Neurophysiol 2003;114:1615-27. state. Clin Neurophysiol 2007;118:597-605.
9. Robe PA, Dubuisson, Bartsch S, Damas P, Laureys S.
Favourable outcome of a brain trauma patient despite 16. Kane NM, Butler SR, Simpson T. Coma outcome predic- 24. Koelsch S, Heinke W, Sammler D, Olthoff D. Auditory
bilateral loss of cortical somatosensory evoked potential tion using event-related potentials: P3 and Mismatch processing during deep propofol sedation and recovery from
during thiopental sedation. JNNP 2003;74:1157-8. Negativity. Audiol Neurootol 2000;5:186-91. unconsciousness. Clin Neurophysiol 2006;117:1746-59.
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ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I 15

Neuropathology Article
The Significance of Diffuse Axonal Injury:

how to diagnose it and what does it tell us?
T
raumatic brain injury (TBI) is a leading cause of The damaged axons are more widespread and seen in sev-
death and disability worldwide. TBI can be classi- eral parts of the brain, including those in the supratento-
fied as missile and non-missile. The latter can fur- rial and infratentorial brain regions, such as the cerebel-
ther be subdivided as focal and diffuse damage, which lum and pons. DAI should be considered as a serious and
often overlaps (Table 1).1 significant head injury. However, it is graded according to
the severity of pathology, clinical presentation and likeli-
Table 1: Classification of Traumatic Brain Injury. hood of survival (Table 2).2
Traumatic Brain Injury Table 2: Grading of Diffuse Axonal Injury Tibor Hortobágyi is Senior
(according to Adams et al.2) Lecturer at the Institute of
Psychiatry and Honorary
missile Non-missile (blunt)
Diffuse Haemorrhage Lesions in Consultant Neuropathologist at
Axonal in corpus dorsolat- King’s College Hospital in
Focal damage Diffuse damage London. His main fields of
Injury callosum eral rostral research are neurodegeneration,
brainstem brain trauma and stroke.
Contusion Axonal Injury
Laceration Vascular Injury Grade 1 Present Absent Absent
Haemorrhage Hypoxic/Ischaemic damage Grade 2 Present Present Absent
Infection Swelling
Grade 3 Present Present Present
Focal damage includes contusions, which are usually The identification of diffuse damage to the axons in the
superficial bruises of the brain, affecting the cortex and in brain should follow a detailed histological examination of
more severe cases also the underlying white matter. many parts of the brain which are more susceptible to
Contusions often have a triangular shape, with a wide axonal injury. These include the frontal parasagittal white
Safa Al-Sarraj is a Consultant
base on the surface of the crest of a gyrus as opposed to matter, parietal lobe (including deep white matter), ante- Neuropathologist and Head of
ischaemic damage, which tends to be more severe and at rior corpus callosum, posterior corpus callosum, basal Clinical Neuropathology at King's
the depths of the sulci. They are classified as i) indirect ganglia (to include the internal capsule), cerebellum (to College Hospital NHS Foundation
Trust and Director of the Brain
(‘contre-coup’), frequently seen in the anterior and inferi- include middle cerebellar peduncle) and pons (to include
Bank. He has interest in research
or surfaces of the frontal and temporal lobes, and ii) direct dorsolateral rostral brainstem).3,4 in neuropathology of head injury
(‘coup’) contusions seen at the site of severe impact on the Axonal injury can be caused by immediate (primary) and Motor Neurone Disease.
surface of any region of the brain. Lacerations occur when axotomy which occurs at the time of injury or delayed
the damage is severe enough to cause tearing of the lep- (secondary) axotomy which evolves over a few minutes or
Correspondence to:
tomeninges. Bleeding is common after TBI. Intracranial hours after impact. In the majority of cases of head injury, Tibor Hortobágyi, MD, PhD,
haemorrhage may develop over a period of time, which secondary axotomy is the major mechanism.5 The focal MRCPath, EFNP,
may extend into the subarachnoid space causing sub- damage to the axonal cytoskeleton is followed by forma- Departments of Clinical
tion of axonal swellings and varicosities proximal to the Neuropathology & Clinical
arachnoid haemorrhage (SAH); other causes of SAH
Neuroscience,
include skull fracture with tearing and/or dissection of site of injury. These swellings contain accumulated mate- Academic Neuroscience Building,
arteries such as the vertebral arteries. Extradural rial which cannot be transported due to disruption of Institute of Psychiatry,
haematoma (EDH) is usually associated with skull frac- axoplasmic flow.6 Therefore, the axonal swelling usually Denmark Hill, London,
occurs some time after head trauma and indicates some SE5 9RS, UK
ture and torn meningeal arteries, whereas subdural
Email. tibor.hortobagyi@
haematoma (SDH) results from the tearing of the bridg- period of survival. iop.kcl.ac.uk
ing veins in particular those related to the superior sagit-
tal sinus. Focal infection is frequently a complication of Detection of axonal injury
skull fracture and contamination with bacteria. Several histological methods can detect damaged axons
Diffuse damage includes diffuse axonal injury with variable degrees of sensitivity and depend on mini-
(DAI)(see below), diffuse vascular injury and diffuse mum survival time of patients after head trauma (Table
hypoxia/ischaemia. Diffuse vascular injury results from 3). The most widely used and most reliable method is
shear stress and traction of parenchymal blood vessels amyloid precursor protein (APP) immunohistochem-
resulting in petechial haemorrhages. Diffuse hypoxic- istry.7 APP (Table 4) is a membrane glycoprotein which is
ischaemic damage sometimes accompanies TBI, especial-
ly in patients with raised intracranial pressure (over 30
mmHg) and severe long-lasting hypotension. Table 3: Methods and their time dependency to detect
axonal injury
Classification of axonal injury Silver 15-18h
Axonal injury is frequently a consequence of traumatic Table 3: Methods and their time
H&E 24h
brain injury which may cause other focal damage in the dependency for detection of
brain like contusions, lacerations or haemorrhage. Immunohistochemistry: GFAP 5d < axonal injury (AI) in paraffin
Depending on the severity of trauma, the axonal injury CD68 36-48h embedded human brain tissue.
(Silver: silver impregnation
can be focal, multi-focal or diffuse. In focal and multi- Neurofilament 60 min technique; H&E: Haematoxylin
focal axonal injury the damaged axons are seen in one or and eosin stains; The other
Chromogranin A
few locations in the supratentorial parts of the brain, methods listed are
mainly in the corpus callosum and internal capsule, but Cathepsin D immunohistochemical. GFAP:
Glial Fibrillary Acidic Protein;
not in the infratentorial brain regions. Diffuse axonal SNAP-25 SNAP-25: Synaptic Protein-25;
injury (DAI) is usually associated with rapid angular APP < 35 min APP: Amyloid Precursor
(rotational) acceleration and deceleration of the brain. Protein).

Table 4: The role and significance of Amyloid Precursor Protein (APP).
Amyloid precursor protein (APP)

• ubiquitous membrane glycoprotein coded on chromosome 21
• alternate splicing and proteolytic processing - > 3 major subtypes
Physiological/pathological significance:
• cell-adhesion
• ?neuroprotective (via secreted N-terminal fragments) Figure 1: Immunohistochemical detection of APP without (left) and with (right) antigen
• amyloidogenic proteolytic pathways / β-Amyloid plaque retrieval. The accumulation of APP proximal to the site of axonal injury is visualised only
• fast anterograde axoplasmic transport / synaptic function after application of antigen retrieval techniques.
/ accumulation proximal to AI
• APP is a sensitive marker of AI of any cause
• non-specific for traumatic aetiology of AI
In axonal injury:
• size and staining pattern correlates with survival time
• helpful but not sufficient for exact timing of injury
produced in cell bodies and neurones. Its major physiological role is in cell
adhesion, neuroprotection and synaptic function. This is the same protein
which is implicated in β-amyloid plaque formation in Alzheimer’s disease
following an abnormal proteolytic cleavage by an enzyme called gamma
secretase. To this end, head injury is a known environmental risk factor for
Alzheimer’s disease, in particular in subjects carrying the apolipoprotein E
(APOE) ε 4 allele as an additional genetic risk factor.8
In normal circumstances, APP travels from the neurone to the periph-
eral axons via fast transport mechanism which cannot be detected by
immunohistochemistry. This transport is an ATP-dependent process, and
the speed is influenced by axonal diameter and age of the individual. If
there is axonal disruption for any reason, including trauma, the APP can
accumulate at the site of injury and can be demonstrated by immunohis-
tochemistry. It is important that very small amounts of protein are Figure 2: APP immunohistochemistry in a case of severe brain trauma. Note the strong
detected in these cases, so antigen retrieval techniques (e.g. microwaving), labelling of damaged axons on a clear background with fusiform swellings, thickened
careful optimisation of the immunohistochemical method and selection filaments and globules.
of the antibody are crucial. When such issues are addressed, APP
immunohistochemistry can be detected within one hour survival period,
and in some cases following 35 minutes survival period.9 With an opti-
mised method, including microwave and citrate pre-treatment of histo-
logical sections, APP immunohistochemistry can detect axonal injury
with post TBI survival times of less than 60 minutes and a minimum of
35 minutes.9
The APP intensity increases with time up to 24 hours. After that, the
staining may become more granular, slightly pale after a few days and dis-
appears after one month or less.
It has been demonstrated that wide sampling and APP immunohisto-
chemistry can determine the cause of axonal injury in most cases.10
Differential diagnosis
It is important to emphasise that axonal injury can not only be caused by
trauma but by different mechanisms such as ischaemia, hypoglycaemia,
inflammation, haemorrhage, drugs, alcohol and even ageing.11 Therefore,
APP immunohistochemistry should be considered to be a sensitive, but
not specific, marker of axonal injury. The distinction between traumatic
and other causes of axonal injury can be difficult and, in many cases, only
a probability can be established. The most frequent problem is to distin-
Figure 3: APP immunohistochemistry in a case of acute cerebral ischaemia. There is a
guish hypoxic-ischaemic damage to the axons from that caused by trau- heavy granular staining revealing an ill-defined, geographical pattern on a ‘dirty’
ma. This is made more complicated by virtue that ischaemia and hypox- background.
ia are frequent occurrences and sometimes considered an integral part of
head injury. Many cases of head injury are associated with subdural or
extradural haematoma which can cause brain shifting and herniation and The ‘shaken baby syndrome’
subsequent axonal injury due to vascular damage. One of the rare causes of head injury in children is non-accidental injury
In traumatic head injury, the APP immunohistochemistry usually (shaken baby syndrome or shaken-impact baby syndrome). The brain
reveals well-defined fusiform swellings of different sizes, beaded and usually shows no evidence of contusions or lacerations but swelling and
thickened filaments and globules which, in some places, are seen along oedema associated with ischaemic damage. Therefore, the damaged
white matter tracts (such as those seen in the internal capsule and corpus axons in these cases are more frequently seen in a pattern consistent with
callosum) with no granular background (Figure 2). In cases of hypoxia ischaemic damage than traumatic damage.13,14 There are two possible
and ischaemia or other vascular damage, the APP immunohistochemistry explanations for the mechanism of brain swelling and hypoxia in shak-
is usually associated with heavy deposition in ill-defined areas, and some- en baby syndrome.15 The first is an alteration in the blood brain barrier
times a geographical pattern (following the areas of ischaemia) with a leading to oedema and increased intracranial pressure followed by
heavy granular background.12 (Figure 3). ischaemia. However, recently it has been proposed that focal damage to

Figure 4: Histological
appearances at the level
of an injured
cranio-cervical
junction in a case of
paediatric non-
accidental injury
(‘Shaken Baby
Syndrome’).
a) (top image)
Haematoxylin & Eosin
stain reveals the dilated
axons as pink globules. PRESCRIBING INFORMATION – UK AND ROI
b) (bottom image)
Immunohistochemistry REBIF® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION
highlights the dilated
REBIF® 22 MICROGRAMS SOLUTION FOR INJECTION
axons, rich in
REBIF® 44 MICROGRAMS SOLUTION FOR INJECTION
accumulated APP.
Interferon beta-1a
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44 µg Interferon beta-1a in 0.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy
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initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform
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the medulla may cause cardio-respiratory arrest and ischaemia; the axonal depressive disorders and those with antecedents of suicidal ideation. Advise patients to report
damage can be demonstrated in a proportion of victims by APP immuno- immediately any symptoms of depression and/or suicidal ideation. Closely monitor patients
exhibiting depression and treat appropriately. Consider cessation of therapy. Administer with
histochemistry (Figures 4a & b). caution in patients with a history of seizures and those receiving anti-epileptics, particularly if
epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening
Conclusions of their condition during initiation of therapy. Patients should use an aseptic injection technique
Diffuse axonal injury is a significant traumatic brain injury which involves and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients
widespread damage to axons in supra- and infratentorial parts of the brain should consult their doctor before continuing injections. If multiple lesions occur, discontinue
Rebif until healed. Use with caution in patients with history of significant liver disease, active liver
and is graded 1-3, according to the severity of pathology and the likelihood disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy,
of survival. It should be differentiated from focal or multi-focal axonal at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver
injury. APP immunohistochemistry is the most sensitive tool to detect dam- dysfunction appear. Treatment has potential to cause severe liver injury including acute hepatic
aged axons. However, it is not specific as it could occur in any other condi- failure. Full haematological monitoring is recommended at months 1, 3 and 6 and periodically
tion which causes damage to the axons, such as ischaemia. APP immunohis- thereafter. All monitoring should be more frequent when initiating Rebif 44. New or worsening
thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if
tochemistry can detect axonal injury within one hour and as early as 35 abnormal every 6 – 12 months. Use with caution in, and closely monitor patients with, severe
minutes after trauma, which has medico-legal implications. renal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may develop
and are associated with reduced efficacy. If a patient responds poorly and has neutralising
References antibodies, reassess treatment. Use with caution in patients receiving medicines with a narrow
1. Graham DI, Gennarelli TA, McIntosh TK. Trauma. Greenfield’s Neuropathology, 7th Ed (eds.: therapeutic index cleared by cytochrome P450. Women of childbearing potential should use effective
Graham DI & Lantos PL) Arnold, London. 2002;823-88. contraception. Limited data suggest a possible increased risk of spontaneous abortion. During
2. Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR. Diffuse axonal injury in lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give
head injury: definition, diagnosis and grading. Histopathology 1989;15:49-59. supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider
3. Geddes JF, Vowles GH, Beer TW, Ellison DW. The diagnosis of diffuse axonal injury: implications temporarily lowering or interrupting dose. Very common: flu-like symptoms, injection site
for forensic practice. Neuropathol Appl Neurobiol 1997;23:339-47. inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia,
4. Geddes JF, Whitwell HL, Graham DI. Traumatic axonal injury: practical issues for diagnosis in leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue,
medicolegal cases. Neuropathol Appl Neurobiol 2000;26:105-16. rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea,
5. Maxwell WL, Povlishock JT, Graham DL. A mechanistic analysis of nondisruptive axonal injury: a depression, insomnia. Serious side effects include: injection site necrosis, hepatitis with or without
review. J Neurotrauma 1997;14:419-40. icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema
6. Otsuka N, Tomonaga M, Ikeda K. Rapid appearance of beta-amyloid precursor protein multiforme-like skin reactions, seizures, thromboembolic events, suicide attempt. Consult the
immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab Summary of Product Characteristics for more information relating to side effects.
injury. Brain Res 1991;568:335-8. Legal category POM
7. Sherriff FE, Bridges LR, Gentleman SM, Sivaloganathan S, Wilson S. Markers of axonal injury in Price
post mortem human brain. Acta Neuropathol (Berl) 1994;88:433-9. Rebif 8.8 and 22: 6 (0.2 ml) + 6 (0.5 ml) syringes - £586.19
8. Nicoll JA, Roberts GW, Graham DI. Amyloid protein, APOE genotype and head injury. Ann N Y Rebif 22: 12 syringes (0.5 ml) - £650.13
Acad Sci 1996;17:271-5. Rebif 44: 12 syringes (0.5 ml) - £863.28
9. Hortobágyi T, Wise S, Hunt N, Cary N, Djurovic V, Fegan-Earl A, Shorrock K, Rouse D, Al- For prices in Ireland, consult distributors Allphar Services Ltd.
Sarraj S. Traumatic axonal injury in the brain can be detected using β-APP immunohistochemistry Marketing Authorisation Holder and Numbers:
in a minimum of 35 minutes after head injury to human adults. Neuropathol Appl Neurobiol. Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003 & 006
2007;33:226-37. For further information contact:
10. Reichard RR, Smith C, Graham DI. The significance of β-APP immunoreactivity in forensic prac- UK: Merck Serono, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX.
tice. Neuropathol Appl Neurobiol 2005;31: 304-13. Tel: 020 8818 7373.
11. Niess C, Grauel U, Toennes SW, Bratzke H. Incidence of axonal injury in human brain tissue. Republic of Ireland: Merck Serono, 3013 Lake Drive, Citywest Business Campus, Dublin 24.
Acta Neuropathol (Berl) 2002;104:79-84. Tel: 01 4661910
12. Lambri M, Djurovic V, Kibble M, Cairns N, Al-Sarraj S. Specificity and sensitivity of betaAPP in Date of Preparation: September 2007
head injury. Clin Neuropathol 2001;20:263-71.
13. Geddes JF, Vowles GH, Hackshaw AK, Nickols CD, Scott IS, Whitwell HL. Neuropathology of Adverse events should be reported to Merck Serono - see contact
inflicted head injury in children. II. Microscopic brain injury in infants. Brain. 2001;124:1299-306. details within PI. Information about adverse event reporting in the UK
14. Geddes JF, Hackshaw AK, Vowles GH, Nickols CD, Whitwell HL. Neuropathology of inflicted can be found at www.yellowcard.gov.uk.
head injury in children. I. Patterns of brain damage. Brain. 2001;124:1290-8.
15. Gerber P, Coffman K. Nonaccidental head trauma in infants. Childs Nervous System. Date of preparation: October 2007
2007;23:499-507. REB07-0146

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Date of preparation: October 2007
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Neurology and Literature
‘Neurological literature’: Cognitive Disorders
C
ognitive disorders may not perhaps lend verbal output. These phenomena are the result of a ‘left
Dr Andrew Larner is the editor of
themselves well to literary description, in the our Book Review Section. He is a
cerebral infarction’ (66), although interestingly the
way that, for example, headache disorders, as Consultant Neurologist at the patient is left handed (57) which may complicate any
almost purely subjective states, do. Nonetheless, some Walton Centre for Neurology and simple interpretation. Mrs Stilson also seems to have an
attempts have been made, examples of which are Neurosurgery in Liverpool, with a ‘out of body experience’ near the end of the play (74).
particular interest in dementia and
reviewed here. cognitive disorders. He is also an
Kopit’s work is also mentioned in the context of a
Honorary Apothecaries' Lecturer (non-fictional) case of global aphasia characterised
Amnesia in the History of Medicine at the by recurrent utterances, sometimes also known as
Amnesia is, of course, a staple of Hollywood hokum University of Liverpool. verbal stereotypies, stereotyped aphasia, or monopha-
(see Box: film buffs will surely be able to recall more Correspondence to: sia.9 This of course differs from the total anarthria of
Dr Andrew Larner, Walton Centre for Neurology
examples); it is perhaps as popular a theme as the and Neurosurgery, Lower Lane, Fazakerley, Liverpool,
the locked-in syndrome reported from the inside, as it
maverick cop or the wrongly accused. Loss of person- L9 7LJ, UK. E. a.larner@thewaltoncentre.nhs.uk were, by Bauby.10
al identity is a frequent aspect of these formulaic
screen episodes of amnesia, and recovery an Apraxia
inevitable part of the filmic denouement, both fea- the protagonist develops memory problems and goes David Perkin identified a possible case of ‘dressing
tures suggestive of psychogenic amnesia or fugue. In missing after a head injury (season four: Mr Monk apraxia’ in Arnold Bennett’s novel Clayhanger (1910)
connection with loss of personal identity, boys of a Bumps His Head). The police surmise amnesia (= loss in the character of Darius Clayhanger, a portrait per-
certain vintage will recall that this is the fate which of identity), but Monk’s psychiatrist Dr Kroger states haps based on the illness of the author’s father, Enoch
befell the quintessential toy doll action hero Action that what they suggest is very rare and thinks some Bennett. Perkin suggests a pathological diagnosis of
Man, sadly without recovery. kind of dissociative state more likely. Although Monk Pick’s disease confined to the parietal lobes in Bennett
Amnesia as a feature of Alzheimer’s disease has is apparently unaware of his identity, nonetheless his père, based on analogy with a case described by
also attracted screen portrayals: Mia Farrow in Forget obsessive-compulsive traits persist, which allows him Lhermitte.11 Certainly a corticobasal degeneration
Me Never (1999), Julie Christie in Away From Her to solve a murder despite not knowing that he is a syndrome with the neuropathological substrate of tau-
(2006), and perhaps most famously Judi Dench in Iris detective. positive Pick body Pick’s disease has been described
(2001), based on John Bayley’s memoir of his wife Iris Other authors have been fascinated by memory, for on occasion.12 However, the symptom of dressing
Murdoch’s illness, the linguistic consequences of example Jane Austen in Mansfield Park.3,4 As pointed out apraxia is now regarded as a disorder of visuopercep-
which have also been chronicled, more objectively, by Papanicolaou in his textbook on amnesia,5 the vil- tual function rather than an apraxia per se.
through analysis of novels written at three stages of lagers of Macondo in One Hundred Years of Solitude by Difficulty dressing is one feature manifested by a
the author’s career.1 Gabriel Garcia Marquez suffer loss of memory for object character in the short story No One’s Guilty by the
Memory problems are also the defining character- names following an ‘insomnia plague’, in response to Argentinian author Julio Cortázar (1914-1984), which
istic of Mr Forgetful, number 14 in the Mister Men which they paste labels to objects bearing their names has been interpreted as an example of ideomotor aprax-
series of children’s books by Roger Hargreaves: and functions.6 Poor sleep quality is of course not an ia. Other symptoms mentioned may be thought repre-
entrusted with a message, Mr Forgetful forgets it, in as uncommon accompaniment, and of probable aetiologi- sentative of alien hand, dystonia, myoclonus and pos-
much as he is only able to pass on a garbled version, cal significance, in memory clinic attenders complain- tural instability, which together have been suggested to
only to recall the correct message later, suggesting his ing of poor memory, although in the case of Marquez constitute the gestalt of corticobasal degeneration.13
problem is one of retrieval rather than encoding and the trope is probably symbolic rather than naturalistic.7
storage. In Harry Potter and the Chamber of Secrets, Agnosia
Gilderoy Lockhart, Hogwarts’ Defence Against the Aphasia Previous articles in ACNR have alluded to possible
Dark Arts teacher, threatens Harry and Ron with a Wings by Arthur Kopit,8 initially conceived as a radio- cases of agnosia, specifically visual object agnosia in
‘Memory Charm’ after admitting he was not in fact the play and later adapted for the stage, portrays a woman Anton Chekhov’s short story The Kiss (1887),4 and
perpetrator of the heroic deeds described in his with post-stroke aphasia. Kopit was prompted to exam- prosopagnosia afflicting Lewis Carroll’s Humpty
books, but he is ‘impaled upon his own sword’, ine this issue when his father suffered a stroke, Dumpty in Through the Looking-Glass and What Alice
according to Dumbledore, when the charm backfires although the author describes the piece as ‘speculation Found There (1872).14
on the threshold of the Chamber of Secrets.2 informed by fact’ (xv) and not a case study. The central
An ‘amnesia drug’ given as a ‘shot’ is available at the character, Emily Stilson, is in her 70s when she suffers References
Supreme Headquarters of the Alien Defence a stroke. She has what appears to be a fluent aphasia 1. Garrard P, Maloney LM, Hodges JR, Patterson K. The effects of very
early Alzheimer’s disease on the characteristics of writing by a
Organisation (SHADO) in the 1970s Gerry and Sylvia with paraphasias and neologisms, which the author renowned author. Brain 2005;128:250-60.
Anderson serial UFO, to be administered to individu- describes, evidently advisedly from the material con- 2. Rowling JK. Harry Potter and the Chamber of Secrets. London:
als who unwittingly come into contact with aliens or tained in his introduction, as jargon (42). We hear her Bloomsbury, 1998;220:224,244.
SHADO. In the US TV serial Monk, about the detective words from both her own and her medical auditors 3. Harris J. Jane Austen’s art of memory. Cambridge: CUP, 1989.
Adrian Monk who has obsessive-compulsive disorder, point of view, indicating the lack of self-monitoring of 4. Larner AJ. Jane Austen on memory; Anton Chekhov on agnosia.
Advances in Clinical Neuroscience & Rehabilitation 2005;5(2):14.
5. Papanicolaou AC (ed.). The amnesias: a clinical textbook of memo-
Some films featuring characters with amnesia/memory loss ry disorders. Oxford: Oxford University Press, 2006:129,240.
6. Garcia Marquez G. One hundred years of solitude. London: Picador,
Shattered (1991). Tom Berenger: car crash, coma, memory erased, unfaithful wife, torrid affair, etc, etc …. 1978[1967]:43,45-7.
The Long Kiss Goodnight (1996). Amnesiac suburban housewife Samantha, aka Charly (Geena Davis), was a ruthless 7. Bell M. Gabriel Garcia Marquez: solitude and solidarity. London:
assassin: “Like Charly’s alter ego .. you may have trouble remembering what happened once its all over” (Time Out). MacMillan, 1993: 43-52.
Jackie Chan’s Who Am I? (1998). Any more explanation required?? 8. Kopit A. Wings. London: Eyre Methuen, 1979.
Memento (2000). Shelby (Guy Pearce) suffers from a kind of memory loss whereby he remembers life before the murder 9. Hale S. The man who lost his language. A case of aphasia (Revised
of his wife but is unable since then to recall anything for more than a few minutes. edition). London: Jessica Kingsley, 2007:31,39-40,64,138,144,201.
Santa Who? (2000). Santa (Leslie Nielsen) suffers amnesia after crashing his sleigh into the car of a Scrooge-like TV 10. Bauby JD. The diving-bell and the butterfly. London: Fourth Estate,
1997.
reporter.
11. Perkin GD. Arnold Bennett and medicine: with particular reference
The Bourne Identity (2002). Amnesiac (Matt Damon) was deadly CIA assassin, now the target of his former employers; to his description of dressing apraxia. BMJ 1981;283:1666-8.
memory still troubled in The Bourne Supremacy (2004). 12. Doran M, du Plessis DG, Enevoldson TP, Fletcher NA, Ghadiali E,
Blind Horizon (2003). Amnesiac (Val Kilmer) believes US president in peril. Larner AJ. Pathological heterogeneity of clinically diagnosed corti-
Gothika (2003). Psychiatrist (Halle Berry) develops amnesia after a car crash, then is incarcerated in her own hospital cobasal degeneration. J Neurol Sci 2003;216:127-34.
accused of murdering her husband. An every day tale of psychiatry practice? 13. Merello M. Julio Cortázar quotes on normal and abnormal move-
50 First Dates (2004). Amnesiac Lucy (Drew Barrymore) must be wooed afresh each day by would-be Don Juan ments: magic realism or reality? Mov Disord 2006;21:1062-5.
(Adam Sandler). 14. Larner AJ. The neurology of “Alice”. Advances in Clinical
Neuroscience & Rehabilitation 2005;4(6):35-6.

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initial dose should not exceed 25 U per eye but this can be subsequently increased. The total dose should not skin rash, muscle weakness inflicted injury. Spasmodic torticollis: Common: dysphagia, muscle weakness, back
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No more than 50 U should be given at any one injection site. Contra-indications: Known hypersensitivity PL29978/0001. Marketing Authorisation Holder: Merz Pharmaceuticals GmbH, 60048 Frankfurt Main,
to Botulinum neurotoxin type A or to any of the excipients, generalised disorders of muscle activity (e.g. Germany. Further information available from: Merz Pharma UK Ltd., 260 Centennial Park, Elstree Hill,
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contains albumin a derivative of human blood. Prior to administration the physician must make himself familiar References: 1. Benecke R et al. Neurology 2005; 64: 1949-1951.2. Roggenkämper P et al. J Neural
with the patient’s anatomy and any changes due to surgical procedures. Side effects related to spread of Transm 2006; 113: 303-312. 3. XEOMIN® protein load. Data on File, Merz Pharma UK Ltd.
botulinum toxin have resulted in death which in some cases was associated with dysphagia, pneumonia 4. Jost WH et al. Drugs 2007; 67(5): 669-683. 5. XEOMIN® Summary of Product Characteristics.
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at the address above, by e-mail to UKdrugsafety@merz.com or on 0845 009 0110 BLEPHAROSPASM AND SPASMODIC TORTICOLLIS IN ADULTS
Neurology in India
Movement Disorders in India
T
he ancient texts of the Indian system of medicine does not remain in the nervous system. These patients do
‘Ayurveda’, describes Parkinsonism and tremors as not improve with levodopa.16
early as 5000-3000 BC.1 Surgery was the treatment of choice for PD before lev-
odopa was introduced. In 1963, Prof Varma attempted to
Parkinsonism lesion the ventrolateral thalamic nucleus by injecting alco-
The Ayurvedic physician, Charaka, was possibly the first hol via needle inserted through the foramen ovale to con-
to describe Parkinson’s disease (PD) in his treatise trol tremors.17,19 Using this outpatient procedure he
“Charaka Samhitha” where he called it ‘Kampavata’, liter- stopped advancing the needle when the tremors stopped,
ally meaning ‘tremors of neurological origin’. thinking he had reached the planned target, the VL thala-
Interestingly, the treatment recommended in Ayurveda mic nucleus. However, when these lesions were mapped Professor Uday Muthane is an
for PD is the seeds of Mucuna Pruriens whose extract using the Schaltenbrand atlas, they were located in the Additional Professor of Neurology
at the National Institute of Mental
contains levodopa. All this was known much before James subthalamic nucleus. This anatomical localisation was Health & Neurosciences in
Parkinson described this disease in modern times. confirmed at autopsy, using a stereotaxic atlas and, recent- Bangalore, India. His areas of
The prevalence of PD in Indians is lower than people of ly, using MRI.18 interest are Parkinson's Disease
European origin. Parsis who immigrated to India cen- In the modern era, surgical treatment for advanced PD and other Movement Disorders.
He is interested in its etiopatho-
turies ago from Persia have a much higher prevalence of has resurfaced as a treatment and Doshi and Bhatt report- genesis, genetics, epidemiology
PD than the Indians.2 A recent epidemiological study ed depression following deep brain stimulation of the sub- and its social aspects.
from Kolkata showed a low prevalence (Crude Prevalence: thalamic nucleus possibly due to spread of the stimulation
45.8 and Age Adjusted Prevalence: 71.6 per 100,000) of to the limbic region of this structure. Kishore et al have
Correspondence to:
Parkinsonism.3 On the contrary, the prevalence of PD in also observed motor improvement following stereotactic Department of Neurology,
Anglo-Indians, a mixed race from marriage between a lesions to treat levodopa-induced dyskinesia but this is National Institute of Mental
European man and an Indian woman is about 40% lower dependent on the volume of lesions in the ventral globus Health & Neurosciences,
than the prevalence in the Caucasian population.4 pallidus and suggested different anatomical substrates Hosur Road,
Bangalore, 560029,
Normal Indians have 40% fewer melanised nigral neu- might be involved in controlling ‘off signs’ and dyskinesia. India.
rons than British Caucasians and these neurons are not lost Behari et al evaluated the quality of life (QoL) in PD Email: umuthane@usa.net
with increasing age.5 The number of melanised nigral neu- patients and observed that female gender, depression,
rons between the British and Nigerians did not differ signif- reduced independence, higher levodopa dose (>400
icantly suggesting that factors other than neuronal num- mg/day) and UPDRS scores were associated with worse
bers contribute to differential susceptibility to PD between QoL.19
non-white and white races.6 Medicines and surgical interventions have improved
Genetic studies in familial PD have shown that alpha- the quality of life of PD patients but are still expensive and
synuclein,7 Parkin,8-11 LRRK2,10 PINK and DJ-1 mutations unaffordable to many living in developing countries.
occur in a small number of Indian patients. SCA2 com- Managing PD in Indians where only 3% have health
monly causes ataxia in the Indians but Ragothaman et al insurance is a challenge. Indian patients spend nearly 40%
have described a family with homozygous SCA2 muta- of their average gross income to buy medicines and
tion, who presented as levodopa responsive parkinson- despite the costs of treating PD in India being lower than
ism. However, unlike the ataxic phenotype that have slow in developed nations, optimal treatment is still out of
saccades, they had normal eye movements. These patients reach for many Indian patients.20
develop motor fluctuations and dyskinesia, hence early in
the illness they can be mistaken as PD. Furthermore these Chorea
SCA2 patients with parkinsonism develop slow saccades, Rheumatic fever is still common in India and chorea still
psychosis and dementia about six years after disease occurs frequently. The prevalence of Huntington’s disease
onset.12 (HD) in Indians is not known, it occurs in 1.75 per 100,
Manganese-induced Parkinsonism is common in the 000 population of Indians living in the United Kingdom.21
manganese mine workers in India. These patients typical- Salem et al, found that the distribution of alleles (D2642
ly walk on their toes and fall frequently as they have and D4S127) in Indian HD patients are similar to West
severely impaired postural reflexes. They typically have a European populations and suggest that this admixture
pathological laughter and deep pigmentation of gums, possibly occurred when British troops were located in
palate and uvula, and their parkinsonism does not South India during various wars.22
improve with levodopa.13,14 Bhatt et al reported parkinson- Wali et al reported a large South Indian family with
ism on exposure to household pesticides.15 In Japanese autosomal dominant paroxysmal kinesogenic chorea-
encephalitis-endemic regions, parkinsonism occurs in thetosis (PKC) and onset in early childhood.
~80% of patients during the acute illness but a long-term Choreathotosis was precipitated by activities such as
follow up showed that it persists in only a few adults, hyperventilation (46%), swimming (23%), exposure to
whilst in children they develop dystonia. JE antibodies cold (30.8%) and prolonged exercise (23%). This family
and antigen were absent in the CSF of patients who devel- has a second PKC mutation localised to the long-arm of
oped these movement disorders, showing that the virus chromosome 16q13-q22.1.23
Patients in India present with a wide variety of movement

disorders and these pose challenges, especially in terms of
treatment, given the therapeutic limitations due to a near
total lack of health insurance
Neurology in India
Dystonia present with osteomalacia.32,33 Wilson’s disease is though a common cause

Naiya et al evaluated DYT1 mutations in patients with primary dystonia of dystonia and other movement disorders in Indians. Patients present
from eastern India and found three reported and two novel mutations with neurological deficits (69%) in the first or second decade of life and
suggesting these mutations rarely cause dystonia in Indians.24 Behari et al ~15% have hepatic dysfunction.34 Autopsy shows caudate atrophy (100%)
identified chewing betel nut with tobacco increased the risk of develop- or central pontine myelinolysis (83%)35 and treatment with D-
ing Meige syndrome.25 Ragothaman et al reported task specific dystonia Penicllamine can initially worsen the neurological deficits in ~50% of
while playing the Indian percussion instruments ‘tabla’ and wind instru- patients.
ment ‘Nadaswaram’.26 Dystonia due to Niemann-Pick type C, GM1 gan-
gliosidosis and Hallervorden Spatz have been reported.27-30 GM1 gan- Myoclonus
gliosidosis patients have generalised dystonia with prominent facial dys- Subacute Sclerosing Encephalitis (SSE) still unfortunately occurs and is
tonia, severe dysarthria and normal eye movements, with Gaucher-like a common cause of myoclonus as measles vaccination is still not
foam cells in the marrow and their MRI shows typical symmetrical puta- mandatory and is often unaffordable. It can occur in children and
menal lesions. The diagnosis is confirmed by deficiency of beta-galactosi- adults. Adult SSE occurs at a mean age of 20.9 years with the patients
dase. Dystonia following Japanese encephalitis occurs in children, and presenting with generalised myoclonus, behavioural changes, seizures,
typically develops one to three weeks after the acute illness. Some patients cognitive decline, visual impairment and extrapyramidal features like
relapse after a partial recovery suggesting a biphasic illness pattern. parkinsonism and dystonia. SSE still poses diagnostic challenges for cli-
During the second phase, patients develop behavioural changes, dystonia, nicians in India.36 Neuronal ceroid lipfuscinosis is another cause of
peri-oral dyskinesia and drooling.31 myoclonus (83.8%) in children and is associated with regression of
milestones (83.3%), chorea (50%), visual impairment (42%), ataxia
Tremors (33.3%) and abnormal behaviour (17%). Eye examination shows optic
Infantile tremors syndrome has been described in Indian infants from atrophy (50%), macular degeneration (33.3%) and retinitis pigmentosa
poor, malnourished families. Tremors are generalised and are prominent- (8.3%). Skin biopsy shows characteristic PAS and Luxol Fast Blue (LFB)
ly seen in distal extremities, appearing suddenly after a brief febrile illness positive, autofluorescent intracellular ceroid material in neurons and
lasting for six weeks. Frontal lobe biopsy showed features of encephalitis astrocytes.37
and meningoencephalitis but CSF examination is normal and negative
for common viruses. Conclusion
Patients in India present with a wide variety of movement disorders and
Wilson’s Disease these pose challenges, especially in terms of treatment, given the thera-
Wadia and Dastur reported that 30% of Wilson’s disease cases in India peutic limitations due to a near total lack of health insurance.
References
1. Muthane UB, Bhatt MH, Wadia NH. Parkinson's Disease and other Akinetic disorders. In: 19. Behari M, Srivastava AK, Pandey RM. Quality of life in patients with Parkinson's disease.
Wadia NH, editor. Neurological Practice: An Indian Perspective. New Delhi: Elsevier, Parkinsonism Relat Disord 2005;11(4):221-6.
2005:353-65. 20. Ragothaman M, Govindappa ST, Rattihalli R, Subbakrishna DK, Muthane UB. Direct
2. Muthane U, Jain S, Gururaj G. Hunting genes in Parkinson's disease from the roots. costs of managing Parkinson's disease in India: concerns in a developing country. Mov
Medical Hypothese 2001; 57(1)(2001):51-5. Disord 2006;21(10):1755-8.
3. Das SK, Biswas A, Roy T, Banerjee TK, Mukherjee CS, Raut DK et al. A random sample 21. Shiwach RS, Lindenbaum RH. Prevalence of Huntington's disease among the Indian immi-
survey for prevalence of major neurological disorders in Kolkata. Indian J Med Res grants from the Indian subcontinent. Br J Psychiatry 1990;157:598-9.
2006;124(2):163-72. 22. Saleem Q, Muthane U, Verma IC, Brahmachari SK, Jain S. Expanding colonies and
4. Ragothaman M, Murgod UA, Gururaj G, Kumaraswamy SD, Muthane U. Lower risk of expanding repeats. Lancet 2002;359(9309):895-6.
Parkinson's disease in an admixed population of European and Indian origins. Mov Disord 23. Valente EM, Spacey SD, Wali GM, Bhatia KP, Dixon PH, Wood NW et al. A second parox-
2003;18(8):912-4. ysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family
5. Muthane U, Yasha TC, Shankar SK. Low Numbers and No Loss of Melanized Nigral of genes which give rise to paroxysmal disorders on human chromosome 16. Brain
Neurons with Increasing Age in Normal Human Brains from India. Ann Neurol 2000;123:2040-5.
1998;43:283-7. 24. Naiya T, Biswas A, Neogi R, Datta S, Misra AK, Das SK et al. Clinical characterization and
6. Muthane UB, Chickabasaviah YT, Henderson J, Kingsbury AE, Kilford L, Shankar SK et evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurol Scand
al. Melanized nigral neuronal numbers in Nigerian and British individuals. Mov Disord 2006;114(3):210-15.
2006;21(8):1239-41.
25. Behari M, Sharma AK, Changkakoti S, Sharma N, Pandey RM. Case-control study of
7. Nagar S, Juyal RC, Chaudhary S, Behari M, Gupta M, Rao SN et al. Mutations in the Meige’s syndrome. Result of a pilot study. Neuroepidemiology 2000;19(5):275-80.
alpha-synuclein gene in Parkinson's disease among Indians. Acta Neurol Scand
26. Ragothaman M, Sarangmat N, Jayaram S, Swaminath P, Muthane U. Task-specific dysto-
2001;103(2):120-2.
nia in tabla players. Movement Disorders 2004.
8. Madegowda RH, Kishore A, Anand A. Mutational screening of the parkin gene among
27. Muthane UB, Yasha TC, Shankar SK, Christopher R, Cooney AM, Kaneski CR et al. A
South Indians with early onset Parkinson's disease. J Neurol Neurosurg Psychiatry
new variety of dystonia with a phenotype mimicking Niemann-Pick type C or a new variant
2005;76(11):1588-90.
of Niemann Pick type C disease? Mov.Disord. 1998;13(suppl 2):96. Ref Type: Abstract
9. Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S et al. Molecular pathogenesis of
28. Muthane UB, Yasha TC, Kaneski CR, Shankar SK, Gayathri N, Christopher R et al.
Parkinson's disease: identification of mutations in the Parkin gene in Indian patients.
Clinical Features of Adult GM1 Gangliosidosis : Report of three Indian patients and Review
Parkinsonism Relat Disord 2006;12(7):420-6.
of 40 cases. Movement Disorders. In press.
10. Punia S, Behari M, Govindappa ST, Swaminath PV, Jayaram S, Goyal V et al.
Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease 29. Muthane U, Chickabasaviah Y, Kaneski C, Shankar SK, Narayanappa G, Christopher R et
patients. Neurosci Lett 2006;409(2):83-8. al. Clinical features of adult GM1 gangliosidosis: report of three Indian patients and review
of 40 cases. Mov Disord 2004;19(11):1334-41.
11. Biswas A, Maulik M, Das SK, Ray K, Ray J. Parkin polymorphisms: risk for Parkinson's dis-
ease in Indian population. Clin Genet 2007; 72(5):484-6. 30. Muthane UB, Shetty R, Panda K, Yasha TC, Jayakumar PN, Taly AB. Hallervordern Spatz
12. Ragothaman M, Muthane U. Homozygous SCA 2 mutations changes phenotype and has- disease and acanthocytes. Neurology 1999;53(8):32.
tens progression. Movement Disorders 2008 (In Press). 31. Pradhan S, Gupta RK, Singh MB, Mathur A. Biphasic illness pattern due to early relapse in
13. Wadia NH. Manganese intoxication in Indian mines. In: Bogaert LV, Kafer JP, Poch G, Japanese-B virus encephalitis. J Neurol Sci 2001;183(1):13-8.
Lopez L, editors. Tropical Neurology proceedings of the 1st International Symposium 32. Wadia NH, Dastur DK. Wilson's Disease in four Indian families (Clinical, Genetical and
Beunos Aires. Beunos Aires, Argentina: 1962:272-7. Biochemical aspects). Neurology 1963;11:1-18.
14. Veerendrakumar M, Gourie-Devi M, Chandra SV. Neurological disorders in chronic indus- 33. Dastur DK, Manghani DK, Wadia NH. Wilson's disease in India. I. Geographic, genetic,
trial exposure to manganese. Indian Academy of Neurology. 1990. (Abstract) and clinical aspects in 16 families. Neurology 1968;18:21-31.
15. Bhatt MH, Elias MA, Mankodi AK. Acute and reversible parkinsonism due to organophos- 34. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease:
phate pesticide intoxication: five cases. Neurology 1999;52:1467-71. description of 282 patients evaluated over 3 decades. Medicine (Baltimore)
16. Murgod UA, Muthane UB, Ravi V, Radhesh S, Desai A. Persistent movement disorders fol- 2007;86(2):112-21.
lowing Japanese Encephalitis. Neurology 2001;57(12):2313-5. 35. Sinha S, Jha DK, Sinha KK. Wilson's disease in eastern India. J Assoc Physicians India
17. Varma RM. Percutaneous cheomthalamectomy for Parkinsonism. Neurology India 2001;49:881-4.
1964;12:54-60. 36. Prashanth LK, Taly AB, Ravi V, Sinha S, Arunodaya GR. Adult onset subacute sclerosing
18. Muthane UB, Varma RM, Sundarajan P, Hegde T, Jayakumar PN, Shankar SK. panencephalitis: clinical profile of 39 patients from a tertiary care centre. J Neurol
Percutaneous trans-Foramen Ovale approach to Subthalamic Nucleus (Varma's technique): Neurosurg Psychiatry 2006;77(5):630-3.
A shorter route and economical technique in the surgical management of Parkinson's 37. Sinha S, Satishchandra P, Santosh V, Gayatri N, Shankar SK. Neuronal ceroid lipofusci-
Disease. Mov.Disord. 1998:13(Suppl 2);71. (Abstract) nosis: a clinicopathological study. Seizure 2004;13(4):235-40.

Association of British Neurologists Trainees
ABNT - Message from the Chair
T
he ABN Spring Meeting was held jointly this year specialty fellowships in neurology. Although these are in Andrew Kelso is Chair of the
with the British Society of Clinical the very early stages of development, and their future ABNT. He is an SpR in Neurology
in Edinburgh, with a special inter-
Neurophysiologists, at Croke Park Stadium in prospects are by no means clear, they are probably going to est in epilepsy. He is also a mem-
Dublin, and featured a programme that is increasingly be shorter (around six months), and are designed to pro- ber of the BMA Junior Doctors
geared towards education, and the needs of trainees. vide sub-specialty training in centres of excellence. There Conference Agenda Committee,
Further details of this meeting will be reported separately is scope to develop them further, including more wide- Junior Doctors Committee and
Scottish Junior Doctors
in ACNR, but I’d like to draw your attention to the ABNT spread implementation, but funding arrangements are the Committee.
forum that was held at the close of the meeting. obvious limiting factor. The background to, and pros and
In the past this has been poorly attended, due partly to cons of post-CCT fellowships are summarised in Figure 1.
an unappealing 7.30am slot! Attendance this year was
Correspondence to:
much better, attracting between 30 and 40 trainees, and a A potential solution Association of British
number of related issues were discussed. Opinion was canvassed from trainees with regard to the Neurologists,
above issues, and discussion ranged around possible solu- Ormond House,
European Working Time Directive (EWTD) tions. In general, it was felt that widespread implementa- 27 Boswell Street,
London, WC1N 3JZ, UK.
The UK will move to a 48-hour working week in August tion of Post-CCT fellowships in neurology was not in the T. +44 (0)20 7405 4060,
2009, potentially causing huge problems for the NHS. In best interest of patients or training, but that a more limit- W. www.theabn.org
neurology, some centres have already moved to a partial ed introduction would be of definite benefit to individual Email. info@theabn.org
shift system, where others are trying to maintain an on-call trainees. There was siginificant support from trainees for
system: to be compliant with EWTD, most on-call rotas a lengthening of training to maintain CCT quality in the
need between 10 and 12 middle graders, with obvious face of reduced experience due to EWTD, with a recogni-
funding implications. Although the Tooke Report implied tion that neurology should continue to be a consultant-
that EWTD may be enforced with variable efficiency in the led service, and that there was not a place for an extra
future, it is European law at present, and UK employment grade between StR and Consultant. In this context, could
legislation theoretically has to comply. An employee opt subspecialty training could be incorporated as part of
out is a theoretical possibility, and alternative plans exist extra training instead of as a ‘bolt-on’ module?
(such as the Barbados Plan, devised by Remedy UK); both The ABNT urgently needs to know more about your
leave trainees wide open to harassment and undue pres- opinions on this – we will be discussing our concerns fur-
sure from managers, and have significant logistical diffi- ther with TEC and the Neurology SAC, and it’s important
culties. From hospitals where trainees already have to work that we represent you properly during this process. Please
night shifts (either neurology only, or hospital at night), get in touch with your views via the ABN Offices (see con-
with compensatory time off day duties, there are already tact details).
concerns that training is suffering. Although training is
meant to be competency based, this is still blue-printed Next Meeting
onto the reasonable amount of time that an individual can The next ABNT meeting will be on Wednesday 10th
be expected to take to acquire that competency, i.e. is still September in Aviemore.
time based in reality.
Post-CCT Fellowships Figure 1

Post-CCT fellowships
Context The need
Last year, the MMC Programme Board invited bids from Shorter training
all specialties for funded post-CCT fellowships, lasting Perhaps no research experience?
one year. Their stated purpose was to provide extra train- Increasingly competitive job market
ing not covered in standard curriculum, but additionally Recognition that neurology increasingly
sub-specialised
they could help with the ‘bulge’ in trainee numbers, allow-
Potential shortage of consultant jobs
ing trainees to vacate their numbers early, granting a
PMETB imposed restrictions on dual
salary for a year, and assisting in number recycling.
accreditation with neurophysiology
Approximately 100 positions have been awarded to the
applying specialties – the bulk of these are in the surgical
Pros Extra training
specialties, but O&G, anaesthetics and psychiatry have Benefits of national expertise
also been reasonably successful, and JRCPTB has been Improve CV
awarded a few for the medical specialties. Some of the
applications are a bit opaque – the skills they are meant to Cons Non-standard jobs – national terms and
develop are not clearly super-specialist in some cases, and conditions of service may not apply
consultant jobs for these highly specialised trainees are No clearly defined training outcome
still lacking! “Yellow box” (sub-consultant grade)
Completely independently, the ABN Training and threat Loss of 6 month period of grace
Education Committee have opened discussions with sev-
eral of the major neurological charities to develop sub-
Additional web content www.acnr.co.uk
See the website for an additional Case Report:

A Case of Isolated Central Nervous System Vasculitis
by Kalra S, Harries S, Gutowski NJ

07-9811_TYS AD ACNR (A4) 4/2/08 16:18 Page 1
MOVING YOUR PATIENTS
A STEP CLOSER TO FREEDOM

FROM MS DISEASE ACTIVITY
Until now, MS therapies have only been

moderately effective, reducing the annualised
rate of relapse by about one third.*1,2
Available on the NHS for patients with Highly

Active RRMS, TYSABRI® offers a proven:
81% reduction in annualised relapse rate

vs placebo over 2 years (p < 0.001)**3,4
64% reduction in the risk of disability
progression, sustained for 24 weeks,
as assessed over 2 years (p = 0.008)**3,4
* There have been no head to head Prescribing information: TYSABRI® (natalizumab) assessments should be considered. Once PML has been excluded, dosing of TYSABRI® may
prospective studies to compare Presentations: 300 mg concentrate for solution for infusion. Colourless, clear to resume. If patients develop PML, the dosing of TYSABRI® must be permanently discontinued.
slightly opalescent solution. Each ml of concentrate contains 20 mg of natalizumab. Other Opportunistic Infections: Other opportunistic infections have been reported with use of
TYSABRI and other MS therapies
When diluted, the solution for infusion contains approximately 2.6 mg/ml of natalizumab. TYSABRI®. If an opportunistic infection is suspected, dosing with TYSABRI® is to be
** Patients with ≥ 2 relapses in Indications: Single disease modifying therapy in highly active relapsing remitting multiple suspended until such infection can be excluded through further evaluation. Hypersensitivity:
previous year and ≥ 1 Gd+ lesion sclerosis for the following patient groups: patients with rapidly evolving severe relapsing Hypersensitivity reactions have been associated with TYSABRI®, including serious systemic
at baseline remitting multiple sclerosis or patients with high disease activity despite treatment with a reactions. These reactions usually occur during the infusion or up to 1 hour after completion
beta-interferon. Dosage and Administration: The recommended dosage is 300 mg of infusion. If a hypersensitivity reaction occurs TYSABRI® must be permanently discontinued.
administered by intravenous infusion once every 4 weeks. The diluted solution is to be Immunogenicity: In the case of disease exacerbations or infusion related events the presence
infused intravenously over 1 hour at a rate of approximately 2 ml/minute and patients are of antibodies should be evaluated. Treatment should be discontinued if persistent antibodies
References: to be observed during infusion and for 1 hour after the completion of the infusion for signs develop. Stopping Therapy: If therapy is discontinued be aware that TYSABRI® has
1. Galetta SL, et al. Arch Intern Med and symptoms of hypersensitivity reactions. TYSABRI® therapy is to be initiated and pharmacodynamic effects for up to 12 weeks. Pregnancy and lactation; If patients become
2002; 162: 2161–2169. supervised by specialised physicians experienced in the diagnosis and treatment of pregnant while taking TYSABRI®, discontinuation of TYSABRI® should be considered. Patients
2. Polman CH, et al. NEJM 2006; neurological conditions, in centres with resources for management of hypersensitivity receiving TYSABRI® should not breastfeed their infant. General: Physicians must discuss the
354(9): 899–910.
reactions and timely access to MRI. Continued therapy must be carefully reconsidered benefits and risks of TYSABRI® therapy with the patient and provide them with a Patient Alert
3. TYSABRI SmPC, Biogen Idec Ltd.
4. TY00-032, Data on file. in patients who show no evidence of therapeutic benefit beyond 6 months. Card. Patients should be instructed that if they develop any infection they should inform their
Biogen Idec Ltd. Patients treated with TYSABRI® must be given the Patient Alert Card. physician that they are being treated with TYSABRI®. Drug interaction: Combination with
Contraindications: Hypersensitivity to natalizumab or to any of the beta-interferons or glatiramer acetate is contraindicated. The safety and efficacy of TYSABRI®
Date of preparation: excipients, progressive multifocal leukoencephalopathy (PML); in combination with other immunosuppressive and antineoplastics therapies have not been
January 2008 patients with increased risk of opportunistic infections, fully established. Concurrent use of these agents with TYSABRI® may increase the risk of
TY00-PAN-22968 including immunocompromised patients (including those infections including opportunistic infections. No formal interaction studies have been
currently receiving immunosuppressive therapies or those conducted with TYSABRI® in humans. Undesirable Effects: The most commonly reported
immunocompromised by prior therapies, e.g. mitoxantrone symptoms are: Infections and infestations: Urinary tract infection, nasopharyngitis. Immune
or cyclophosphamide); combination with beta-interferons system disorders; urticaria. Nervous system disorders; headache, dizziness. Gastrointestinal
or glatiramer acetate; known active malignancies; disorders; vomiting, nausea. Musculoskeletal and connective tissue disorder; arthralgia.
children and adolescents. TYSABRI® is not General disorders and administration site conditions; rigors, pyrexia, fatigue. Other less
recommended for use in patients aged over 65 years. common events include: hypersensitivity reactions, infusion reactions, PML, other
Special Warnings and Precautions; CNS: Use of TYSABRI® has opportunistic infections, immunogenicity. For further information regarding adverse events
been associated with increased risk of progressive multifocal please refer to the Summary of Product Characteristics. Legal Classification: POM. Pack
leukoencephalopathy (PML). Before initiation of treatment with size: 1 vial/pack. NHS Price: UK; £1130/vial. Ireland; €1636.85/vial. Package
TYSABRI®, an MRI image of the patients should be available Quantities: 300 mg/15 ml. Product Licence Number; EU/1/06/346/001. Product
3 months within starting treatment. Patients must be monitored Licence Holder: Elan Pharma International Ltd., Monksland, Athlone, County Westmeath,
at regular intervals for any new or worsening neurological Ireland. Date of last revision of Prescribing Information: August 2006. Please refer to
symptoms or signs suggestive of PML. If new neurological the Summary of Product Characteristics for further information.
symptoms occur, further dosing should be suspended until PML
For the UK only: Information about adverse event reporting can
has been excluded. If the symptoms are suggestive of PML, or
if any doubt exists, further evaluation, including MRI scan
be found at www.yellowcard.gov.uk. Adverse events should be
(compared with pre-treatment MRI) and repeat neurological reported to Biogen Idec Ltd., on 08000 286639
Neurosurgery Article
Prevention and Treatment of Vasospasm Following

Subarachnoid Haemorrhage
D
elayed ischaemic neurological deficit (DIND) is a analysis found that there was no difference in the inci-
major cause of morbidity and mortality following dence of DINDs between coiling and clipping.13,14
aneurysmal subarachnoid haemorrhage (SAH).
This condition is potentially preventable and treatable. Pathophysiology
The pathogenesis of the condition is unclear although DINDs may be due to focal or global ischaemia and do
vasospasm is of paramount importance. The diagnosis of not necessarily occur in arterial territories directly relat-
DIND secondary to vasospasm remains contentious and ed to the site of the aneurysmal rupture. Whether the
is reliant upon clinical status and cerebral imaging tech- ischaemia is due to spasm of the large arteries,
niques. Therapeutic interventions require high dependen- microvascular insufficiency or some other unelucidated
cy care and are not always effective. In this article the his- mechanism is uncertain. Most pharmacological Reuben Johnson is a Specialist
torical recognition of cerebral vasospasm is described, the research has focused on the role of vasospasm in caus- Registrar in neurosurgery at the
broad pathophysiological mechanisms that may be ing DINDs. It appears that the initial trigger for John Radcliffe, Oxford. He has
involved are outlined and the management options are vasospastic ischaemic deficits is leakage of blood into trained in Glasgow, London and
Cambridge. He began in neuro-
reviewed. the subarachnoid space. Fisher et al. noted that surgery at Atkinson Morley's
vasospasm appears to be associated with the blood load Hospital and Hurstwood Park
Introduction in the subarachnoid space. 15 Oxyhaemoglobin and Neurological Centre and complet-
In 1949, the Australian neurologist Edward Graeme platelets have been implicated as molecular agents that ed a DPhil in Oxford.
Robertson hypothesised that arterial spasm may be must be present in the subarachnoid space in order for
responsible for post-subarachnoid haemorrhage (SAH) vasospasm to occur.16,17 Various molecular mechanisms
cerebral infarction.1 In 1951, Denny-Brown attributed have been implicated in the development of DIND
post-SAH deterioration to cerebral vasospasm.2 The downstream of this ‘blood-trigger’. These include
same year two Americans, Ecker and Riemenschneider, reduced endothelial synthesis of the vasodilator nitric
demonstrated angiographic spasm in six patients with oxide (NO); reduced vasodilatatory action of nitric
aneurysmal SAH.3 In the mid 1960s Stornelli and oxide; and increased release of the vasoconstrictor
French reported that angiographic vasospasm indicated endothelin-1 (ET-1). The possible imbalance of NO and
a poor prognosis.4 Allcock and Drake conducted a thor- ET-1 in mediating the protein kinase C dependent con- Hilary Madder is Clinical Director
ough angiographic examination of 83 patients before tractile system in vessel walls has provided potential of Neuro-Intensive Care at the
and after treatment of their intracranial aneurysms and new therapeutic strategies by means of NO activa- John Radcliffe, Oxford. She trained
found evidence of vasospasm in over 40% of patients.5 tors/donors and ET-1 antagonists. In addition free rad- in Australia and the United
Kingdom. Her specialist interests
They reported that patients with vasospasm were more ical generation may be a contributing factor to the are cerebral protection and the
likely to have a poor outcome and concluded that arte- pathogenesis of DINDs (Figure 1).18-20 management of vasospasm.
rial spasm was the main cause of morbidity and mortal-
ity in patients with ruptured intracranial aneurysms.
Correspondence to:
➝
The time course of vasospasm was shown by Fischer, Reuben Johnson,

who reported that neurological deterioration occurred Department of Neurosurgery,
➝
➝
in one third of SAH patients, and was maximal between and Neuroscience Intensive Care
days 2 and 4 following the bleed.6 West Wing,
John Radcliffe Hosptial,
➝
In 1970 the normal sizes of the carotid artery and the

➝
Headley Way,
major cerebral branches were reported enabling objec- Headington,
tive assessments of vasospasm.7 Weir et al. reported that Oxford, OX3 9DU, UK.
the ratio of intracranial to extracranial vessel diameter Email. reubenjohnson@
doctors.org.uk
was reduced in some subarachnoid patients.8 They also
demonstrated that this vasospasm was maximal
between days 4 to 8 following the initial bleed and had
resolved by day 12. In the International Cooperative
Study, Kassell et al. showed that the clinical and radio-
logical features of vasospasm were discordant. Delayed Figure 1. Pathophysiology of vasospasm.
ischaemic neurological deficits (DINDs) occurred in
30% of patients whereas angiographic vasospasm was
observed in up to 70% of cases.9 In addition DINDs Assessment of a patient with a DIND
were also noted to occur in the absence of angiographic Clinical assessment, transcranial Doppler ultrasonogra-
vasospasm in some cases. phy (TCDs), cerebral perfusion imaging and digital
subtraction angiography (DSA) are all used in the clin-
Epidemiology ical arena to assess cerebral blood flow parameters in
In the UK aneursymal subarachnoid haemorrhage has patients with a DIND.
an incidence of approximately 8-10 per 100,000 per
year, although population-based studies suggest that the Clinical assessment
incidence may be higher.10 DINDs are a major cause of Clinical assessment is a robust method of assessing the
morbidity and mortality following subarachnoid haem- functional integrity of cerebral tissue and is carried out
orrhage.11,12 National Audit Data on 2420 SAH patients by careful close monitoring of neurological status. A
found no statistically significant difference in the inci- diagnosis of DIND is made when other possible causes
dence of DINDs between coiled and clipped patients.12 of neurological deterioration such rebleeding, hydro-
Even though The International Subarachnoid cephalus, seizures and electrolyte abnormalities have
Aneurysmal Trial (ISAT) provided Grade 1 evidence for been excluded. Neurological deterioration may include
improved one year outcome for coiling over clipping of focal deficits such as unilateral limb weakness or dys-
small anterior circulation aneurysms, a recent meta- phasia, or global impairment such as confusion or

and negative predictive values of 94% for velocities <120 cms-1.27 One
of the interesting findings of Vora et al’s study was that the Lindegaard
ratio did not alter the predictive value of TCDs. Fontanella et al. under-
took a prospective study of 786 patients with anterior circulation
aneurysmal SAH where any patient with a MCA velocity of > 120 cms-
1
underwent cerebral angiography. They reported that TCDs had a 97%
predictive value in middle cerebral artery spasm.28 TCD’s have a dis-
tinct advantage over angiography in that they are less expensive, non-
invasive and can be used at the bedside to monitor response to treat-
ment. Certainly TCD’s are user dependent and provide more reliable
data if serial measurements are recorded in individual patients.29 TCDs
should be viewed as a useful adjunct in the management of DIND
patients when used appropriately.
Cerebral perfusion imaging

Vasospasm revealed on cerebral angiography. A . Left internal carotid artery injection The numerous modalities available include positron emission tomog-
showing a ruptured MCA aneursym (1) with associated vasospasm in the proximal
vessel (2). B. The aneurysm has now been coil occluded (3) and the proximal vessel is no raphy (PET), xenon-enhanced computed tomography (Xe-CT), single-
longer in spasm. photon emission computed tomography, and CT- perfusion tech-
niques. CT-perfusion is less time-consuming and more readily avail-
Figure 2. Vasospasm revealed on cerebral angiography.
able and therefore appears set to become a widespread tool in the
detection of early vasospasm.30 Xe-CT scanning protocols are well
described and can provide evidence of cerebrovascular reactivity if
used in conjunction with CO2 provocation testing. PET is not widely
available but does help determine not only the cerebral blood flow in a
DIND patient but also the oxygen uptake (oxygen extraction fraction)
and cerebral metabolic rate (CMRO2). Such studies assess the degree of
coupling between CBF and brain metabolism and may provide an
insight into the reasons for the discordance between the prevalence of
angiographic vasospasm and DIND. Functional MR imaging is ham-
pered to some extent by the restless nature of many of the patients with
DINDs.
Digital Subtraction Angiography (DSA)

The evolution of non-invasive techniques to assess cerebral perfusion
has reduced the utilisation of DSA to those cases where an endovascu-
lar therapeutic option is being pursued (Figure 2).
Management
Cerebral vasospasm results in altered autoregulation of cerebral blood
flow and ultimately reduced cerebral perfusion resulting in ischaemic
Figure 3. Diagnosis and management of patients with vasospasm with a secured ruptured damage to the brain. Due to the delayed onset of vasospasm, prophy-
aneurysm.
lactic strategies may be effective. Therapeutic modalities have evolved
that aim to reverse vasospasm and protect potentially ischaemic cere-
bral tissue (Figure 3).
increased drowsiness. Several risk factors have been identified which
independently predict symptomatic vasospasm. These include blood Hypertensive, Hypervolaemic and Haemodilution
load in the basal cisterns, a Glasgow Coma Scale score of less than 14 at (HHH-therapy)
presentation and rupture of anterior cerebral (ACA) or internal carotid Kosnik and Hunt were the first to report the effects of raising arterial
(ICA) aneurysms.21 Raised troponin levels and the presence of cerebral pressure in cerebral vasospasm in 1974.31 They reported a series of
salt wasting syndrome may also be risk factors for the development of seven patients in whom the neurological deficit was reversed promptly
vasospasm.22,23 by the elevation of systemic blood pressure and found that infarction
was prevented in some of these patients. Kassell et al. carried out a larg-
Transcranial Doppler (TCD) ultrasonography er study in 1982 in which hypertensive therapy and intravascular vol-
Blood flow velocity through the cerebral arteries is inversely propor- ume expansion in a series of 58 patients permanently reversed neuro-
tional to arterial diameter. TCD is used to measure flow velocity and logical deficits in 47 patients and transiently reversed deficicts in four
thereby indirectly assess the severity of vasospasm.24 However, one of patients.32 Since these early studies, HHH-therapy evolved with the
the main conceptual difficulties with TCDs is that flow velocity may be inclusion of haemodilution to augment rheological properties of blood
raised due to increased flow (hyperaemia) or arterial narrowing flow. Although HHH-therapy has not been examined with a ran-
(vasospasm). To help distinguish vasospasm from hyperaemia the domised controlled trial, it has become the mainstay of medical thera-
Lindegaard ratio of middle cerebral flow velocity to extracranial py for the treatment of vasospasm and more recent investigations using
carotid flow velocity is used. A Lindegaard ratio > 6 represents severe cerebral monitoring support its continued use.33 There is a lack of con-
vasospasm.25 Lindegaard et al. also showed that MCA flow velocity > sensus as to how HHH-therapy should be achieved although monitor-
200 cms-1 was predictive of a 3-fold constriction in the diameter of the ing of clinical condition, CVP measurement, arterial BP measurement
artery.25 and serial TCD measurements in a high-dependency setting are com-
One of the criticisms of TCDs has been that they do not correlate monly employed. HHH-therapy is associated with significant compli-
with cerebral blood flow or perfusion as measured by modalities such cations including pulmonary oedema, myocardial ischaemia and elec-
as Xenon CT or PET scanning.26 Despite the conceptual limitations of trolyte abnormalities including dilutional hyponatraemia.34 Raab et al.
TCDs, there is good evidence to support their clinical application. Vora have found that in poor grade subarachnoid patients the use of mod-
et al. compared MCA velocities with angiographic studies in 101 erate hypertension, normovolaemia, and haemodilution may improve
patients retrospectively and 44 patients prospectively and found that cerebral oxygenation but with less complications than aggressive
TCDs had positive predictive values of 87% for velocities >200 cms-1 hypertensive therapy.33 The prophylactic use of HHH-therapy has not

been widely supported and preliminary trials (eNOS) occurs.49 However, a double-blind and colforsin daropate carries the theoretical
have not shown any benefits.35,36 Hypotension randomised trial of EPO versus placebo in 73 benefit of delivering a high dose of vasodila-
and hypovolaemia should be avoided in all patients failed to show any beneficial effect in tor directly to the resistance vessels, clinical
patients at risk of DIND. In future years func- cerebral vasopasm.50 studies have shown vasodilatation to be tran-
tional imaging modalities and invasive cere- sient and without sustained benefit.61,62 In
bral tissue monitoring may lead to refine- Endothelin-receptor antagonists addition vasodilatation may cause an eleva-
ments in the optimisation of cerebral perfu- There has been much interest in agents which tion of intracranial pressure.63 Such strategies
sion augmentation therapy. will redress the putative imbalance in the con- remain experimental.
trol of PKC-dependent contractile mecha-
Calcium antagonists nisms in vasospasm. These include NO Conclusion
Allen et al. reported the first randomised, donors and ET-1 antagonists. The prelimi- DINDs following subarachnoid haemorrhage
double-blind, placebo-controlled trial (RCT) nary results of a randomised clinical series are devastating and are associated with a high
of nimodipine.37 They looked at prophylactic treated with the ET-1 antagonist clazosentan morbidity and mortality rate. The delayed-
use of nimodipine for 21 days following appears to show improvements in CBF in onset of this disorder which appears to be
aneurysmal SAH in 125 patients of good patients with established vasospasm.51 Further associated with vasospasm and impaired cere-
grade and found that nimodipine was effec- work is required in this area. bral perfusion continues to stimulate clini-
tive in reducing neurological deficits. Pickard cians and neuroscientists to find preventative
et al. reported the largest RCT in 1989 which Pharmacological implants and therapeutic treatement strategies. There
included 554 SAH patients.38 Follow-up at 3 Aneurysm surgery provides an opportunity to is no consensus regarding the underlying
months showed that 21 days of nimodipine investigate the effects of local pharmacologi- pathology or the optimal methods to diag-
treatment was effective in reducing the inci- cal treatments as prophylaxis against nose and treat DINDs. Effective management
dence of cerebral infarction by one-third vasospasm. No beneficial effects were report- is demanding on resources and involves input
(22% with nimodipine compared to 33% with ed in the only randomised controlled trial from neurosurgical, neuroradiological and
placebo) and also improved overall clinical published using a thrombolytic agent. 52,53 neurocritical care specialties. A ‘same-hymn-
outcome. At least five other RCTs of prophy- Kasuya et al. reported the effect of placing sheet’ approach may be required within indi-
lactic nimodipine have been carried out. A prolonged-release nicardipine implants in the vidual centres in order to establish consisten-
meta-analysis concluded that the effectiveness basal cisterns after aneurysm clipping. cy of investigation and treatment so that new
of nimodipine had been well demonstrated Although initial results are promising for the therapeutic modalities can be accurately
and supported routine prophylactic nimodip- proximal vessels, the effect is less on the more assessed. Cerebral vasospasm remains a chal-
ine administration.39 Although other calcium distal cerebral circulation and requires further lenge for all clinicians interested in reducing
antagonists such as nicardipine have been investigation.54,55 the adverse outcomes associated with sub-
investigated a systematic review of 27 RCTs arachnoid haemorrhage.
concluded that there was only evidence to
support the prophylactic use of nimodip-
ine.40,41
Magnesium sulphate
Clinical vasospasm is a diagnosis of exclusion
Magnesium is a cerebral vasodilator and may
also have neuroprotective effects by prevent-
ing influx of calcium into injured neurons via
excitatory amino acid receptor blockade. The Endovascular therapies Acknowledgements
preliminary results of the IMASH trial Endovascular techniques employed in the I would like to thank Peter Whitfield for his contribution. I
would also like to thank Mr Richard Kerr for comments on
showed that a 14 day infusion of magnesium therapy of vasospasm include mechanical the first draft. Dr Shavoo Lalloo kindly provided the
sulphate may reduce the incidence of sympto- dilatation of major cerebral arteries using angiogram pictures.
matic vasospasm and justifies the continua- transluminal balloon angioplasty (TBA) and
tion of the study to try and establish a clini- local injection of vasodilator agents. TBA was
cally useful prophylactic treatment.42,43 first reported in 1984 in a series of 33 SAH
References
cases.56 Since that time defined criteria to
1. Robertson EG. Cerebral lesions due to intracranial
Statins determine the applicability of endovascular aneurysms. Brain 1949;72:150-85.
Statins are known to increase the eNOS activ- techniques have been described. 57 These 2. Denny-Brown D. The treatment of recurrent cerbrovas-
ity and theoretically, therefore, may reduce include the absence of an established infarct cular symptoms and the question of ‘vasospasm’. Med
vasospasm. Two small randomised studies on CT scanning, the persistence of neurologi- Clin North Am 1951;35:1457-74.
have demonstrated a reduced incidence of cal deficits despite medical management 3. Ecker A, Riemenschneider PA. Arteriographic demon-
vasospasm in patients treated with simvas- (HHH-therapy) and angiographic evidence of stration of spasm of the intracranial arteries, with refer-
ence to saccular arterial aneurysms. J Neurosurgery
tatin or pravastatin.44,45 In the pravastatin vasospasm in a distribution consistent with 1951;8:660-7.
study the incidence of TCD detected the neurological deficit. 4. Stornelli SA, French JD. Subarachnoid hemorrhage-fac-
vasospasm was reduced by 32% with a Two large studies support a role for TBA in tors in prognosis and management. J Neurosurg
reduced incidence of DIND and mortality. At the management of vasospasm.58,59 In both of 1964;21:769-80.
six months beneficial effects on physical and these TBA improved angiographic spasm in 5. Allcock JM, Drake CG. Ruptured intracranial
psychological aspects of functioning were over 90% of cases and improved clinical status aneurysms – the role of arterial spasm. J Neurosurg
1965;22:21-9.
reported.46 A multicentre randomised con- in 30-40% of patients. However the complica-
6. Fisher CM, Roberson GH, Ojemann RG. Cerebral
trolled trial looking at the potential benefit of tions of TBA include vessel rupture which has vasospasm with ruptured saccular aneurysm- the clini-
simvastatin (40mg for 21 days) in aneurysmal been reported at a rate of 4%.60 Since many cal manifestations. Neurosurgery. 1977;1:245-8.
SAH (STASH) is underway.47 radiologists consider any beneficial effects of 7. Gabrielson T, Greitz T. Normal size of internal carotid,
TBA to be short-lived the technique has not middle and anterior cerebral arteries. Acta Radiol
Diagn (Stockh) 1970;10:1-10.
Erythropoeitin been universally adopted. A peer reviewed
8. Weir B. Grace M, Hansen J, Rothberg C. Time course of
Erytropoietin (EPO) has been found to have publication of the Balloon Prophylaxis of
vasospasm in man. Journal of Neurosurgery.
neuroprotective effects in the central nervous Aneurysmal Vasospasm Study is awaited. 1978;48:173-8.
system.48 It is unclear how this effect is exert- Although the intra-arterial injection of 9. Kassell NF, Sasaki T, Colohan AR, Nazar G.Cerebral
ed although there is evidence to suggest acti- vasodilators such as papaverine, nimodipine, vasospasm following aneurysmal subarachnoid hemor-
vation of endothelial nitric oxide synthase nicardipine, verapamil, milrinone, fasudil, rhage. Stroke. 1985;16:562-72.

10. Pobereskin LH. Incidence and outcome of subarachnoid 28. Fontanella M, Valfrè W, Benech F, Carlino C, Garbossa 45. Tseng MY, Czosnyka M, Richards H, Pickard JD,
haemorrhage: a retrospective population based study. J D, Ferrio M, Perez R, Berardino M, Bradac G, Ducati Kirkpatrick PJ. Effects of acute treatment with pravas-
Neurol Neurosurg Psychiatry. 2001;70:340-3. A. Vasospasm after SAH due to aneurysm rupture of the tatin on cerebral vasospasm, autoregulation, and
11. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams anterior circle of Willis: value of TCD monitoring. delayed ischemic deficits after aneurysmal subarachnoid
HP, Kongable GL. The International Cooperative Study Neurol Res 2007; Aug 31: PubMed ID17767811. hemorrhage: a phase II randomized placebo-controlled
on the Timing of Aneurysm Surgery. Part 1: Overall Prepublication. trial. Stroke. 2005;36:1627-32.
management results. J Neurosurg 1990;73:18-36. 29. McMahon CT, McDermott P, Horsfall D, Selvarajah 46. Tseng MY, Hutchinson PJ, Czosnyka M, Richards H,
JR, King AT, Vail A. The reproducibility of transcranial Pickard JD, Kirkpatrick PJ. Effects of acute pravastatin
12. National Study of Subarachnoid Haemorrhage,
Doppler middle cerebral artery measurements: implica- treatment on intensity of rescue therapy, length of inpa-
National Study of Subarachnoid Haemorrhage
tions for clinical practice. Br J Neurosurgery tient stay, and 6-month outcome in patients after
Clinical Effectiveness Unit, The Royal College of
2007;21:21-7. aneurysmal subarachnoid hemorrhage. Stroke
Surgeons of England, 2006.
30. Kanazawa R, Kato M, Ishikawa K, Eguchi T, Teramoto 2007;38:1545-50.
13. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, A. Convenience of the computed tomography perfusion
Yarnold JA, Sandercock P. International Subarachnoid 47. www.stashtrial.com
method for cerebral vasospasm detection after subarach-
Aneurysm Trial (ISAT) Collaborative Group. noid hemorrhage. Surg Neurol. 2007;67:604-11. 48. Buemi M, Cavallaro E, Floccari F, Sturiale A, Aloisi C,
International subarachnoid aneurysm trial (ISAT) of Trimarchi M, Corica F, Frisina N. The pleiotropic
31. Kosnik EJ, Hunt WE. Postoperative hypertension in the
neurosurgical clipping versus endovascular coiling in effects of erythropoietin in the central nervous system. J
management of patients with intracranial arterial
2143 patients with ruptured intracranial aneurysms: a Neuropathol Exp Neurol 2003;62:228-36.
aneurysms. J Neurosurg. 1976;45:148-54.
randomised comparison of effects on survival, depend- 49. Santhanam AVR, Katusic ZS. Erythropoietin and cere-
ency, seizures, rebleeding, subgroups, and aneurysm 32. Kassell NF, Peerless SJ, Durwood QJ, Beck DW, Drake
bral vascular protection: role of nitric oxide. Acta
occlusion. Lancet. 2005;366:809-17. CG, Adams HP. Treatment of ischaemic deficits from
Pharmacologica Sinica 2006;27:1389-94.
vasospasm with intravascular volume expansion and
14. de Oliveira JG, Beck J, Ulrich C, Rathert J, Raabe A, induced arterial hypertension. Neurosurgery 50. Springborg JB, Moller C, Gideon P, Jorgensen OS,
Seifert V. Comparison between clipping and coiling on 1982;11:337-43. Juhler OS, Olsen NV. Erythropoeitin in patients with
the incidence of cerebral vasospasm after aneurysmal aneurysmal subarachnoid haemorrhage: a double blind
33. Raabe A, Beck J, Keller M, Vatter H, Zimmermann M,
subarachnoid hemorrhage: a systematic review and randomised clinical trial. Acta Neurochir (Wein)
Seifert V. Relative importance of hypertension compared
meta-analysis. Neurosurg Rev 2007;30:22-31. 2007;149:1089-101.
with hypervolemia for increasing cerebral oxygenation
15. Fisher CM, Kistler JP, Davis JM. Relation of cerebral in patients with cerebral vasospasm after subarachnoid 51. Barth M, Capelle HH, Münch E, Thomé C, Fiedler F,
vasospasm to subarachnoid haemorrhage visualized by hemorrhage. J Neurosurg. 2005;103:974-81. Schmiedek P, Vajkoczy P. Effects of the selective
computerized tomographic scanning. Neurosurgery 34. Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, endothelin A (ET(A)) receptor antagonist Clazosentan
1980;6:1-9. Germanson T, Truslowski L et al. Medical complica- on cerebral perfusion and cerebral oxygenation following
16. McDonald RL, Weir BK. A review of hemoglobin and tions of subarachnoid haemorrhage: a report of the mul- severe subarachnoid hemorrhage - preliminary results
the pathogenesis of cerebral vasospasm. Neurosurgery ticentre, cooperative aneurysm study. Participants of the from a randomized clinical series. Acta Neurochir
1985;16:171-6. Multicentre Cooperative Aneurysm Study. Crit Care (Wien). 2007;149: 911-8.
17. Pyne GJ, Cadoux-Hudson TA, Clark JF. Platelets play Med 1995;23:1007-17. 52. Findlay JM, Weir BK, Kassell NF, Disney LB, Grace
an essential role in the aetiology of cerebral vasospasm 35. Solomon RA, Fink ME, Lennihan L. Prophylactic vol- MG. Intracisternal recombinant tissue plasminogen
after subarachnoid haemorrhage. Med Hypotheses. ume expansion therapy for the prevention of delayed activator after aneurysmal subarachnoid hemorrhage. J
2003;60:525-30. cerebral ischaemia after early aneurysm surgery. Results Neurosurg. 1991;75:181-8.
of a preliminary trial. Arch Neurol 1988;45:325-32. 53. Findlay JM, Kassell NF, Weir BK, Haley EC Jr,
18. Hanggi D, Steiger HJ. Nitric oxide in subarachnoid
haemorrhage and its therapeutic implications. Acta 36. Treggiari MM, Walder B, Suter PM, Romand JA. Kongable G, Germanson T, Truskowski L, Alves WM,
Neurochir (Wein) 2006;149:605-13. Systematic review of the prevention of delayed ischaemic Holness RO, Knuckey NW. A randomized trial of intra-
neurological deficits with hypertension, hypervolaemia, operative, intracisternal tissue plasminogen activator for
19. Khurana VG, Sohni YR, Mangrum WI, McClelland and haemodilution therapy following subarachnoid the prevention of vasospasm. Neurosurgery.
RL, O’Kane DJ, Meyer FB, Meissner I. Endothelial haemorrhage. J Neurosurg 2003;98:978-84. 1995;37:168-76.
nitric oxide synthase gene polymorphisms predict sus-
37. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, 54. Kasuya H, Onda H, Takeshita M, Okada Y, Hori T.
ceptibility to aneurysmal subarachnoid haemorrhage
Boone SC, Chou SN, Kelly DL, Weir BK, Crabbe RA, Efficacy and safety of nicardipine prolonged-release
and cerebral vasospasm. J Cereb Blood Flow Metab
Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, implants for preventing vasospasm in humans. Stroke.
2004;24:291-7.
Mellits DE, Bertsch LA, Boisvert DP, Hundley MB, 2002;33:1011-5.
20. Dumont AS, Dumont RJ, Chow MM, Lin C, Johnson RK, Strom JA, Transou CR. Cerebral arterial
Calisaneller T, Ley KF, Kassell NF, Lee KS. Cerebral spasm - a controlled trial of nimodipine in patients with 55. Krischek B, Kasuya H, Onda H, Hori T. Nicardipine
vasospasm after subarachnoid hemorrhage: putative role subarachnoid hemorrhage. N Engl J Med. prolonged-release implants for preventing cerebral
of inflammation. Neurosurgery 2003;53:123-35. 1983;308:619-24. vasospasm after subarachnoid hemorrhage: effect and
outcome in the first 100 patients. Neurol Med Chir
21. Qureshi AL, Sung GY, Razumovsky AY, Lane K, Straw 38. Pickard JD, Murray GD, Illingworth R, Shaw MD,
(Tokyo). 2007;47:389-94.
RN, Ulatowski JA. Early identification of patients at Teasdale GM, Foy PM, Humphrey PR, Lang DA,
risk for symptomatic vasospasm after aneursymal sub- Nelson R, Richards P, Sinar J, Bailey S, Sken A. Effect of 56. Zubkov YN, Nikiforov BM, Shustin VA. Balloon
arachnoid haemorrhage. Crit Care Med 2000;28:984- oral nimodipine on cerebral infarction and outcome catheter technique for dilatation of constricted cerebral
90. after subarachnoid haemorrhage: British aneurysm arteries after aneurysmal SAH. Acta Neurochir (Wein)
nimodipine trial. BMJ 1989;298:636-42. 1984;70:65-79.
22. Yarlagadda S, Rajendran P, Miss JC, Banki NM,
Kopelnik A, Wu AH, Ko N, Gelb AW, Lawton MT, 39. Barker FG, Ogilvy CS. Efficacy of prophylactic nimodip- 57. Eskridge JM, McAuliffe W, Song JK, Deliganis AV,
Smith WS, Young WL, Zaroff JG. Cardiovascular pre- ine for delayed ischaemic deficit after subarachnoid Newell DW, Lewis DH Mayberg MR, Winn HR.
dictors of in-patient mortality after subarachnoid hem- hemorrhage: a meta-analysis. J Neurosurg Balloon angioplasty for the treatment of vasospasm:
orrhage. Neurocrit Care. 2006;5:102-7. 1996;84:405-14. results of 150 cases. Neurosurgery 1998;42:510-7.
23. Igarashi T, Moro N, Katayama Y, Mori T, Kojima J, 40. Stippler M, Crago E, Levy EI, Kerr ME, Yonas H, 58. Newell DW, Eskridge JM, Aaslid R. Current indications
Kawamata T. Prediction of symptomatic cerebral Horowitz MB, Kassam A. Magnesium infusion for and results of cerebral angioplasty. Acta Neurochir
vasospasm in patients with aneurysmal subarachnoid vasospasm prophylaxis after subarachnoid hemorrhage. Suppl 2001;77:181-3.
J Neurosurg 2006;105:723-9.
hemorrhage: relationship to cerebral salt wasting syn- 59. Muizelaar JP. Balloon prophylaxis for aneurysmal
drome. Neurol Res. 2007;29:835-41. 41. Dorhout Mees SM, Rinkel GJE, Feigin VL, Algra A, vasospasm study (BPAV).
van den Bergh WM, Vermeulen M, van Gijn N. http://clinicaltrials.gov/ct2/show/record/NCT00282
24. Aaslid R, Huber P, Nornes H. A transcranial Doppler
Calcium antagonists for subarachnoid haemorrhage. 893?cond=%22Subarachnoid+Hemorrhage%22&rank
method in the evaluation of cerebrovascular spasm.
Cochrane database of systematic reviews 2007, Issue 3. =35.
Neuroradiology 1986;28:11-16.
Art no.: CD000277.
25. Lindegaard KF, Nornes H, Bakke SJ, Sorteberg W, DOI:10.1002/14651858.CD000277.pub3. 60. Zweinenberg-Lee M, Hartman J, Rudisill N, Muizelaar
Nakstad P. Cerebral vasospasm after subarachnoid JP. Endovascular management of cerebral vasospasm.
42. Wong GK, Chan MT, Boet R, Poon WS, Gin T.
haemorrhage investigated by means of transcranial Neurosurgery 2006;5:139-47.
Intravenous magnesium sulfate after aneurysmal sub-
Doppler ultrasound. Acta Neurochir Suppl (Wein) arachnoid hemorrhage: a prospective randomized pilot 61. Kaku Y, Yonekawa Y, Tsukahara T, Kazekawa K. Super
1988;42:81-4. study. J Neurosurg Anesthesiol. 2006;18:142-8. selective intra-arterial infusion of papaverine for the
26. Minhas PS, Menon DK, Smielewski P, Czosnyka M, treatment of cerebral vasospasm after subarachnoid
43. Wong GK, Chan MT, Poon WS, Boet R, Gin T.
Kirkpatrick PJ, Clark JC, Pickard JD. Positron emission haemorrhage. J Neurosurg 1992;77:842-7.
Magnesium therapy within 48 hours of an aneurysmal
tomographic cerebral perfusion disturbances and tran- subarachnoid hemorrhage: neuro-panacea. Neurol Res. 62. Kassell NF, Helm G, Simmons N, Phillips CD, Cail
scranial Doppler findings among patients with neuro- 2006;28:431-5. WS. Treatment of cerebral vasospasm with intra-arterial
logical deterioration after subarachnoid hemorrhage. 44. Lynch JR, Wang H, McGirt MJ, Floyd J, Friedman AH, papaverine. J Neurosurg 1992;77:848-52.
Neurosurgery 2003;52:1017-25. Coon AL, Blessing R, Alexander MJ, Graffagnino C, 63. Andaluz N, Tomsick TA, Tew JM Jr, van Loveren HR,
27. Vora YY, Suarez-Almazor M, Steinke DE, Martin ML, Warner DS, Laskowitz DT. Simvastatin reduces Yeh HS, Zuccarello M. Indications for endovascular
Findlay JM. Role of Transcranial Doppler Monitoring in vasospasm after aneurysmal subarachnoid hemorrhage: therapy for refractory vasospasm after aneurysmal sub-
the Diagnosis of Cerebral Vasospasm after Subarachnoid results of a pilot randomized clinical trial. Stroke. arachnoid haemorrhage: experience at the University of
Hemorrhage. Neurosurgery 1999;44:1237-47. 2005;36:2024-6. Cincinnati. Surg Neurol 2002;58:131-8.

Case Report
Spontaneous Anterior Intracranial Artery

Dissection: An Important Cause of Stroke in
Young People
I
ntracranial artery dissection (IAD) is rarely reported with relatively subtle symptoms and signs, which could
and possibly underdiagnosed. We present a case of have been easily missed if not considered in the differen-
spontaneous right middle cerebral artery dissection tial diagnosis. See Table 1 for summary characteristics of
causing repeated small ischaemic lesions in the right intracranial dissections.
hemisphere, presenting with frequent, mild intermittent
left-sided neurological symptoms and right-sided Table 1: Key points in intracranial artery dissection.
headache in a 28-year-old female. The presentation was
1. An important cause of TIA/stroke in young people (mean
subtle and diagnosis unusual, highlighting the impor- age 25 years old).
tance of considering dissection as a cause of neurological Gina Kennedy BSc, MBBCh,
deficits with associated headache in young people. 2. Pain (unilateral headache) is a predominant presenting MRCP, PhD, is a Neurology SPR at
Contrast-enhanced magnetic resonance angiography symptom. Frenchay Hospital, Bristol. Her
3. Intracranial artery dissection is less common than first degree in the neurosciences
(CE-MRA) is fast and effective and is the recommended
and a PhD in human vision found-
imaging modality for detecting vascular pathology. extracranial artery dissection. ed her interest in neurology. After
4. Posterior circulation (vertebrobasilar artery) dissection is graduating from Oxford Medical
Introduction more common and more likely to be associated with sub- School, she completed her SHO
training in Bristol and is currently
IAD causing ischaemic stroke or subarachnoid haemhor- arachnoid bleeding than anterior circulation dissection.
developing an interest in stroke.
rhage is rare but possibly under-reported, with only 10-20 5. Risk factors for cerebral artery dissection include trauma,
documented cases to date.1-3 The mean reported age of collagen disorders (fibromuscular dysplasia, cystic medial Dr Patrick Ruane, Bsc, MBChB,
IAD is 25 years,4 however IAD has also been reported in MRCP, is a GP registraar in
necrosis, Marfan’s syndrome, Ehlers-Danlos syndrome
Bristol having completed SHO
children.5,6 Predisposing risk factors include; preceding type IV), and common vascular risk factors (hypertension, training and having attained
trauma and collagen disorders such as fibromuscular dys- smoking, diabetes mellitus, hyperlipidaemia and oral con- MRCP at North Bristol NHS
plasia , cystic medial necrosis,7 moya moya disease, traceptives). trust. A degree in physiology with
Marfan’s syndrome and Ehlers-Danlos syndrome type IV. an emphasis on neurophysiology
6. Contrast-enhanced MRA is the most efficient imaging developed an interest in neurolo-
Common vascular risk factors (hypertension, smoking, modality of choice with comparable diagnositic yield to gy which he now plans to pursue
diabetes mellitus, hyperlipidaemia and oral contracep- formal angiography. as a GP with special interest.
tives) have also been implicated in the pathogenesis of
7. Treatment options include surgery, stenting, anticoagula- Dr Shelley Renowden, BSc,
arterial dissection. There are individual case reports of
tion and antiplatelets, although evidence for favouring MRCP, FRCR, is a consultant neu-
intracranial dissection in the context of orgasmic
one option over another is not yet available. roradiologist based at Frenchay
headache,8 post-coitus9 and post partum,10 but in the Hospital, Bristol and has been in
majority of cases no cause is found. post since January 1996, having
Anterior intracranial dissections typically present with Case report trained previously at the Radcliffe
Infirmary, Oxford. Her main
ipsilateral headache and a contralateral neurological A 28-year-old female presented with a one month histo-
interest is neurointervention and
deficit with altered consciousness. Presentation with sub- ry of progressive left sided sensory symptoms. This neurovascular disease. She cur-
arachnoid bleeding secondary to intracranial dissection is started with intermittent numbness in her left hand, rently works in a tertiary referral
more common in the posterior circulation. involving the thumb and first two fingers, followed by centre for complex neurovascular
disorders and one of her main
Pseudoaneurysm formation is another complication left facial numbness and then left leg numbness. These
objectives, with her clinical col-
resulting from blood tracking through the media to the sensory symptoms would last a few minutes at a time leagues, is to enhance and expand
subadventitial layer and causing dilatation of the outer over a period of several weeks. At the time of initial con- stroke services/treatment in North
wall of the vessel, which tends to occur more commonly sultation, she had mild weakness of her left leg and face. Bristol.
in the posterior circulation but has also been known to The patient also described a continuous right frontal
occur in the anterior circulation.11 Previously, those throbbing headache. There was no previous history of
reported in the literature have usually presented with sig- headache but her mother was known to suffer
nificant morbidity and the diagnosis in some has only migraines. Her only medication was the oral combined
been realised at post-mortem. Those presenting with mild contraceptive pill. Blood pressure was 135/90 with no
transient ischaemic attacks are vanishingly rare, or per- other vascular risk factors.
haps go undiagnosed. An initial MRI brain revealed some high signal abnor-
The diagnostic imaging modalities for intracranial malities, with one predominant lesion in the right corona
artery dissection include formal catheter digital subtrac- radiata suggestive of inflammation or ischaemia (Figure
David Cottrell, MBChB, BSc,
tion angiographic techniques (DSA). Less invasive tech- 1a). A lumbar puncture was acellular with a normal pro- MRCP, PhD, was appointed as a
niques include conventional MRA revealing a ‘rat’s tail’ or tein level and an absence of intrathecal oligoclonal band consultant neurologist and senior
‘string sign’ or T1-weighted axial MRI revealing a double synthesis. An interval brain scan three months later clinical lecturer at Frenchay
Hospital, Bristol in 2005. He spe-
lumen or intramural thrombus.12 Contrast-enhanced showed similar findings with the addition of a further cialises in multiple sclerosis and in
MRA can be performed efficiently in a single breath hold new lesion in the right peritrigonal area. Unusual radio- particular primary progressive
and is comparable to DSA in providing diagnostic infor- logical features on the second scan included restriction of multiple sclerosis.
mation of body arteries13 and provides more extensive and the lesions to the territory of the right middle cerebral
accurate information than conventional MRA. artery and a cavitating appearance of some of the lesions
Computerised tomography angiogram (CTA) can also be which was more in keeping with ischaemia than inflam-
an adequate fast screening modality for cerebral artery mation (Figure 1(a) and 1(b)).
pathology, especially with modern 3-D digital subtraction To investigate further, a contrast-enhanced MRA (CE-
techniques. MRA) was performed. This provided views from the aor-
We present a case of spontaneous right middle cerebral tic arch to the circle of Willis and other intracranial ves-
artery dissection, which resulted in repeated small cere- sels, not routinely included on the normal field of view
bral ischaemic insults in a young female. This presented when assessing the neck vessels in patients with ischaemic

Case Report
stroke. The CEMRA demonstrated a signifi- As imaging availability and techniques

cant M1 stenosis with reduced signal indicat- advance, contrast-enhanced MRA is seriously
ing reduced flow in the more middle cerebral challenging DSA as the primary vascular
circulation (Figure 1c). 3D time of flight imaging modality. It enables fast and reliable
(TOF) MR angiography confirmed the M1 diagnosis of intra and extracranial artery dis-
stenosis (a ‘string sign’) consistent with an section, revealing the true prevalence, course
arterial dissection (Figure 1d), and assumed and outcome of this condition and is the rec-
to be responsible for repeated ischaemic ommended imaging modality of choice in
insults to the right cerebral hemisphere. suspected arterial dissection.
Aspirin was started (75mg once a day) and
the patient was advised to stop the oral com-
bined contraceptive pill and attend regular References
review. At the latest review, she continued to 1. Chaves C, Estol C, Esaola MM, et al. Spontaneous
intracranial internal carotid artery dissection. Arch
complain of headache and residual mild left- Neurol. 2002;59:977-81.
Figure 1(a): T2-weighted axial MRI brain showing high sided sensory symptoms but the initial left 2. Sharif AA, Remley KB, Clark HB. Middle cerebral
signal lesions in the right hemisphere (white arrows). facial and left leg weakness had fully recovered. artery dissection: a clinicopathological study. Neurology.
1995;45:1929-31.
Discussion 3. Lee JS, Bang OY, Lee PH, et al. Two cases of sponta-
neous middle cerebral arterial dissection causing
Intracranial artery dissections can cause sub-
ischemic stroke. Journal of the Neurological Sciences.
arachnoid haemorrhage and ischaemic 2006;250(1-2):162-6.
infarcts. These sequalae have often only been 4. Farrell M, Gilbert J, Kaufmann J. Fatal intracranial
diagnosed at post-mortem in the past but arterial dissection: clinical pathological correlation.
with improved imaging techniques and Journal of Neurology, Neurosurgery and Psychiatry.
1985;48:111-21.
awareness of this condition, intracranial
5. Duncan IC. Clinically occult chronic dissecting
artery dissection is likely to become a more aneurysm of the superior cerebellar artery in a child.
familiar diagnosis. As thrombolysis is a treat- Pediat Radiol. 2005;35:1118-20.
ment option for presumed thrombotic stroke, 6. Danchaivijitr N, Cox T, Saunders DE, et al. Evolution
but not necessarily advisable with dissection, of cerebral arteriopathies in childhood arterial ischemic
stroke. Ann Neurol. 2006;59:620-6.
the aetiology of stroke or transient ischaemic
7. Bahr M, Postler E, Meyermann R. Fatal stroke in a
attacks in a young person should always be patient with carotid and middle cerebral artery dissec-
carefully considered. tion associated with cystic medial necrosis. J Neurol.
Figure 1(b): T1-weighted MRI brain coronal showing The mechanism of ischaemia in intracra- 1996;243(10):722-3.
cavitating lesion in right hemisphere (white arrow). nial artery dissection is thought to be hypop- 8. Szatmary Z, Boukobza M, Vahedi K, et al. Orgasmic
erfusion due to artery occlusion rather than headache and middle cerebral artery dissection. Journal
of Neurology, Neurosurgery and Psychiatry.
embolic events, which are more typical of 2006;77:693-4.
extracranial artery dissections. The anatomy 9. Prabhakaran S, Krakauer JW. Multiple reversible
of the intracranial arterial wall differs from episodes of subcortical ischemia following postcoital
cervical arteries in that the media is thinner middle cerebral artery dissection. Arch Neurol.
2006;63(6):891-3.
and there is no external elastic lamina.
10. Inoue T, Nishimura S, Hayashi N, et al. Postpartum
Haemorrhage as a result of dissection can dissecting aneurysm of the posterior cerebral artery. J
occur between the arterial layers or directly Clin Neurosci. 2007;14(6):576-81.
across the lumen wall and as intracranial arte- 11. Kurino M, Yoshioka S, Ushio Y. Spontaneous dissecting
rial walls are thinner the risk of subarachnoid aneurysms of anterior and middle cerebral artery associ-
bleeding is thought to be higher.4 ated with brain infarction:a case report and review of
the literature. Surg Neurol. 2002;57(6):428-36.
Due to the rare occurrence of intracranial
12. Hosoya T, Adachi M, Yamaguchi K, et al. Clinical and
dissection, there is currently no evidence base neuroradiological features of intracranial vertebrobasilar
to guide treatment. Options include surgery, artery dissection. Stroke. 1999;30:1083-90.
stenting, anticoagulation and antiplatelet 13. Schaefer FK, Schaefer PJ, Altjohann C, et al. A multi-
therapy. We favoured antiplatelet therapy over center, site-independent, blinded study to compare the
diagnostic accuracy of contrast-enhanced magnetic reso-
Figure 1(c): CEMRA reconstructed frontal view anticoagulation given the belief that there is a nance angiography using 1.0M gadabutrol (Gadovist) to
demonstrates normal carotid bifurcations and internal greater risk of intracranial bleeding. There is intraarterial digital subtraction angiography in body
carotid arteries and a right M1 stenosis with reduced
signal in the middle cerebral circulation (white arrow).
an obvious need for a randomised, controlled arteries. Eur J Radiol. 2007;61(2):315-23.
study of treatments in intracranial artery dis- 14. Lyrer P, Engelter S. Antithrombotic drugs for cervical
section. artery dissection. Cochrane Review, Oxford, UK.
2002(1).
The evidence base for treatment of
15. Beletsky V, Nadareishvili Z, Lynch J, et al. Cervical
extracranial dissection is larger but still inad- artery dissection: Time for a therapeutic trial? Stroke.
equate.14,15 In order to try to answer whether 2003;24:2856-60.
we should be using antiplatelets or anticoag- 16. The CADISS Trial Investigators. Antiplatelet therapy
ulation for the treatment of extracranial vs. anticoagulation in cervical artery dissection: ration-
ale and design of the Cervical Artery Dissection in
artery dissection, there is currently a nation- Stroke Study (CADISS). International Journal of
al pilot study underway to determine Stroke. 2007;2:292-6.
whether it would be possible to perform a
large-scale multi-centre, international ran-
domised study which would aim to recruit Correspondence to:
enough patients to provide statistical power Dr Gina Kennedy, BSc, MBBCh, MRCP, PhD,
to be able to reliably compare antiplatelet Institute of Clinical Neurosciences,
Frenchay Hospital, Frenchay Park Road,
with anticoagulation treatment16 (Cervical Bristol, BS16 1EL, UK.
Figure 1(d): A maximum intensity submentovertical
Artery Dissection in Stroke Study: CADISS - T. +44 (0)117 9701212 (switchboard)
projection reconstruction 3D TOF MR angiogram centred personal communication, Professor John F. +44 (0)117 9186672
on the Circle of Willis confirms the presence of a right M1 Norris, St George’s Hospital, London Email: ginakennedy@doctors.org.uk
stenosis, likely to be the result of a dissection. (white arrow). www.dissection.co.uk).

Book Reviews
If you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor, c/o rachael@acnr.com
Multiple Sclerosis Care: a practical manual

Zajicek, Freeman and Porter are to be congratulated for pro- would be useful for doctors who are not experienced in MS
ducing a useful pocket guide to MS. Describing itself as ‘a and its diagnosis and management, notably chapters on dif-
practical manual’, this single volume covers a very wide ferential diagnosis, investigations, and what to say when
range of information, from drug names and doses for neu- patients ask for low dose naltrexone or advice on paying for
ropathic pain to a diagram of the variety of adhesion mole- stem cell ‘treatment’. Indeed, the book would be a useful ref-
cules at the T-cell surface. erence for many non-medically qualified readers, notably
This is not a multi-author book with three editors but a nurse specialist, therapists, and commissioners of MS serv-
volume written by three co-authors, comprising a doctor, a ices.
therapist and a nurse. It seeks to cover the breadth of infor- The authors all practise in the UK and potential buyers
mation useful for MS care. The style is consistent and very may wonder if there would be too much focus on British
readable, without the repetition, or worse occasional contra- practice. Rest assured there is much here that translates to
dictions or variations of emphasis, which can bedevil multi- other countries. The book is strongly evidence-based; nowa-
authored books. The comprehensive content has a logical days treatment trials and science are multinational. While
order, moving from pathology and diagnosis, to disease the examples of service design happen to be British, they are
modifying therapies, relapses and rehabilitation. It covers described in ways which are generalisable, such as who to
symptomatic treatment, equipment and services. include in a multidisciplinary relapse clinic. The internet has
There is generally good use of supporting tables, and a made us a global village and the British and American
number of web citations. The index is helpful but perhaps patient organisations are web-based sources of information.
Authors/editors: John
serves doctors better than other disciplines. For example, if What might be improved in future editions? The dia-
Zajicek, Jennifer Freeman,
you’re aware T-cells are being researched in MS and look up grams and figures could be better presented. Reproducing Bernadette Porter
T-cells under T you find nothing, but looking up MR scans without high production costs may be difficult Published by: Oxford University
immunolog (ical synapse) gets you to a brief introduction to but these images would be better if consistently cropped, if Press
ISBN-13: 978-0-19-856983-1
cellular immunity and self-antigens. extraneous labelling was removed and if abnormalities were
Price: £19.95
The authors are to be commended on some very useful always arrowed. The illustrations for oligoclonal bands and
sections. The description of disease modifying therapies is VERs could be better. The diagram for the blood brain bar- Reviewed by:
comprehensive, strongly evidence-based and appropriately rier could be clearer. The utility of the index for the non- CA Young,
critical. The section on scales is a nice resource for readers specialist could be increased. But these are minor points. If Professor of Neurology,
who need to quickly check what’s in a scale, how it’s admin- you are looking for a single compact volume on MS care, WCNN, Liverpool.
istered and scored, and where they can find a reference or this book would be a good choice that you could read as a
even download a manual. There are many sections which refresher, or use as reference guide.
Insights: Facts and Stories behind Trigeminal Neuralgia

Whether the practise of medicine is predominantly an Art contributed by patients are intermixed with the hard facts
or a Science provokes much heated discussion, especially behind the science of TN. The information is well present-
amongst doctors. Those who dislike a predominantly factu- ed, starting with the basic anatomy and physiology of the
ally based, dispassionate, ‘evidence-based’ method of deal- trigeminal nerve. This is then followed by the presenting
ing with patients have found support by recent publicity on symptoms of TN, investigations, then medical and surgical
‘narrative medicine’. Champions of this argue that doctors management. One chapter is focused specifically on deci-
should spend more time listening to accounts of the sion making to help patients choose the best therapy for
patients’ symptoms and how it impacts on their lives. This them at a given time. In my opinion, this is the crucial chap-
is meant to help to form a ‘therapeutic alliance’ between ter for both patients and doctors to read. It is notoriously
patient and doctor. difficult to compare probabilities. For example, the data on
Detractors of this method of teaching and practising Table five on page 244 would indicate that you are more
medicine however have argued that the pendulum has than two hundred times more likely to die from playing
swung too far. They are worried that too much emphasis on football than from New Variant CJD! However, I suspect
empathy and communication skills distracts from the that this is an oversimplification and information derived
acquisition of core medical knowledge. These new doctors from self selecting populations tends to skew the data.
Author: Joanna Zakrzewska
may be good at hand holding and offering their shoulders There are some minor omissions and errors. For exam- Published by: TNA Trigeminal
to cry on. In addition, they will need to communicate well, ple, it would be useful to highlight the fact that long term Neuralgia Association
especially when they have to tell patients that they are igno- use of carbamazepine for TN does pose a risk of causing ISBN: 0-9672393-4-6
rant of the diagnosis! It is always difficult to judge why and osteoporosis in the population most prone to this condi- Price: $27.95
what the patient narrates in a consultation. Patients’ meth- tion (post-menopausal females). A book like this takes time
Reviewed by:
ods and motives for talking about their symptoms probably to produce and it is not surprising that recent studies sug-
vary according to which doctor they see. The late Richard gesting that TN may be alleviated using triptans were not MS Chong,
Asher in his entertaining essay ‘Talk, Tact and Treatment’ mentioned. Contrary to what is mentioned in the book, Kings College Hospital,
(Richard Asher Talking Sense. Pitman Medical. London checking trigeminal reflexes is part of the neurological London.
1972) has analysed some of these motives. examination and does not need to be done by a neurophys-
Of course, medicine is both an art and a science and this iologist.
book is an attempt to bridge this divide. The stated aim of Overall, I found this book to be very readable and
this book is to inform patients with trigeminal neuralgia informative. It is an excellent summary of TN, and consid-
(TN) and is written by one of the undisputed experts of this ering the price, well worth buying for trainees and estab-
condition. It is also a useful read for neurologists, neurosur- lished clinicians who deal with patients with facial pain.
geons and maxillofacial surgeons who see these patients reg- Make sure you have the facts at your finger tips; your
ularly. The book layout is patient-focused and the vignettes patients will be sure to have it after they read this book.

mother: 365 days a year
ms patient: 15 minutes every Friday
Avonex is the only DMT to show significant
beneficial effects on cognitive dysfunction1
Treatment with Avonex leads to a reduction

in disability over the long term2
Avonex is the only once-weekly treatment for MS
Efficacy that fits lives

Prescribing information is available overleaf
9299 Avonex ACNR A4 297x210.indd 1 14/2/08 10:16:44

Organised by
®
Prescribing information: AVONEX
Presentations: Lyophilised powder for injection for IM administration containing
a 30µg dose (6 million IU) of Interferon beta-1a per vial. Solution for injection in
a pre-filled syringe of 0.5ml for IM administration containing 30µg dose (6 million
IU) of Interferon beta-1a. Indications: For the treatment of ambulatory patients
with relapsing multiple sclerosis characterised by at least 2 recurrent attacks of
MA Healthcare Conferences
neurologic dysfunction (relapses) over the preceding 3-year period without evidence
of continuous progression between relapses. AVONEX® slows the progression of
Forthcoming events include:
disability and decreases the frequency of relapses. AVONEX® is also indicated for
the treatment of patients who have experienced a single demyelinating event with
3rd National
an active inflammatory process if it is severe enough to warrant treatment with
intravenous corticosteroids, if alternative diagnoses have been excluded, and if they
Neuroscience Nursing:
are determined to be at high risk of developing clinically definite multiple sclerosis Back to basics
(see SPC for further information). Treatment should be discontinued in patients who 20th May 2008 Institute of Physics, London
develop chronic progressive multiple sclerosis. Dosage and Administration: The
recommended dosage of AVONEX® in the treatment of relapsing MS is 30µg injected
IM once a week. AVONEX® lyophilised powder presentation should be reconstituted
with the solvent supplied. Treatment should be initiated under supervision of a
Brain and Behaviour:
exploring how neuroscience can support clinical
physician experienced in the treatment of the disease. An antipyretic analgesic is
treatment in child and adolescent mental health
advised to decrease the flu-like symptoms associated with AVONEX® administration.
AVONEX® should not be used in children. Contraindications: Initiation of treatment 8th & 9th September 2008 Institute of Physics, London
in pregnancy. Patients with a history of hypersensitivity to natural or recombinant
interferon beta or any of the excipients. Patients with current severe depression 10th National Conference
disorders and/or suicidal ideation. Precautions: CNS: AVONEX® should be used with
caution in patients with previous or current depressive disorders, in particular to those Parkinson’s Disease:
with antecedents of suicidal ideation. Depression and suicidal ideation are known to responding to mental health issues in Parkinson’s
occur in increased frequency in the multiple sclerosis population in association with 23rd September 2008 Birmingham Children’s Hospital
interferon use. Patients treated with AVONEX® should be advised to immediately report
any symptoms of depression and/or suicidal ideation to their prescribing physician. For full programme details and to book your place at
AVONEX® should be administered with caution to patients with a history of seizures,
to those receiving treatment with anti-epileptics, particularly if their epilepsy is not these or any of our other events please visit our website
adequately controlled with anti-epileptics. Pregnancy and lactation: Initiation of www.mahealthcareevents.co.uk
treatment is contraindicated during pregnancy. Women of child bearing potential
should take appropriate contraceptive measures. If the patient becomes pregnant or
Alternatively call our booking hotline on
plans to become pregnant while taking Avonex, discontinuation of therapy should be 01722 716 007
considered. General: AVONEX® should be used with caution in patients with cardiac
disease, severe renal or hepatic failure or severe myelosuppression, and these patients MA Healthcare Ltd, St. Jude’s Church,
should be closely monitored. Routine periodic blood chemistry and haematology Dulwich Road, London SE24 0PB Fax: 020 7733 8174
tests are recommended during treatment with AVONEX®. Laboratory abnormalities
CONFERENCE FEE INCLUDES ENTRANCE TO THE CONFERENCE,
may also occur which do not usually require treatment. Drug interactions: No formal CPD
LUNCH AND REFRESHMENTS, FULL CONFERENCE
interaction studies have been conducted with AVONEX® in humans. Clinical studies
indicate that corticosteroids or ACTH can be given during relapses. Caution should be DOCUMENTATION AND CERTIFICATE OF ACCREDITATION APPROVED
exercised in combining AVONEX® with medicinal products with a narrow therapeutic
index and dependent on hepatic cytochrome P450 for clearance. Side Effects: The
most commonly reported symptoms are of the flu-like syndrome: muscle ache, fever,
chills, asthenia, headache and nausea. Other less common events include: Body
40 YEARS OF MEDICAL EDUCATION
as a whole: Anorexia, hypersensitivity reactions, weight loss, weight gain, severe
allergic reactions (anaphylactic reactions or anaphylactic shock), syncope. Skin and
appendages: Alopecia, angioneurotic oedema, injection site reaction including pain,
pruritus, rash, urticaria. Digestive system: Diarrhoea, hepatitis, liver function test
abnormalities, vomiting. Cardiovascular system: Chest pain, palpitations, tachycardia,
and vasodilatation and rarely arrhythmia, cardiomyopathy, congestive heart failure.
Haematological system: Thrombocytopenia and rare cases of pancytopenia.
Reproductive system: Metrorrhagia and/or menorrhagia. Nervous system: Anxiety,
dizziness, insomnia, paraesthesia, seizures, depression, suicide (see Precautions).
Transient neurological symptoms that mimic MS exacerbations may occur following
injections. Musculoskeletal system: Arthralgia, pain, transient hypertonia and/
or severe muscular weakness. Respiratory system: Dyspnoea. Autoimmune
disorders, central nervous system disorders and laboratory abnormalities have
been reported with interferons. Rare cases of arthritis, hypo- and hyperthyroidism,
lupus erythematosus syndrome, confusion, emotional lability, psychosis, migraine
and very rare cases of autoimmune hepatitis have been reported with AVONEX®. For
further information regarding adverse events please refer to the Summary of Product
Characteristics. Preclinical Safety: Fertility and developmental studies with a related
form of Interferon beta-1a in Rhesus monkeys show anovulatory and abortifacient
effects at high doses. No teratogenic effects or effects on foetal development were
observed. Legal Classification: POM. Pack Size and UK NHS Price: Box containing
four injections £654. Reimbursed through High Tech Scheme in Ireland. Package
Quantities: Lyophilised Powder: 1 box containing four trays. Each tray contains a
3ml glass vial with BIO-SET device containing a 30µg dose of Interferon beta-1a per
vial, a 1ml pre-filled glass syringe of solvent and one needle. Pre-filled Syringe: 1
box containing four trays. Each tray contains a 1ml pre-filled syringe made of glass
containing 0.5ml of solution (30µg dose of Interferon beta-1a) and one needle.
Product Licence Numbers: EU/1/97/033/002-003. Product Licence Holder: Biogen
Idec Ltd., 5 Roxborough Way, Foundation Park, Maidenhead, Berkshire SL6 3UD,
United Kingdom. Date of last revision of Prescribing Information: September 2006.
Please refer to the Summary of Product Characteristics for further information.
For UK only:
Information about adverse event reporting can be found at www.yellowcard.gov.uk.
Adverse events should also be reported to Biogen Idec Ltd., on 08000 286639.
References:
1. Halper J et al. J Neurosci Nurs 2003; 35: 70-81.
2. Rudick RA et al. Poster presented at ECTRIMS. October 2007; Prague.
Date of preparation: January 2008

AVOO-PAN-22918

Nineteenth Meeting of the
European Neurological Society
June 20 – 24, 2009
Milan, Italy
Neurology: Learning, knowledge, progress and the future
Key symposia:
Management of stroke: from bench to guidelines
The molecular era of neuromuscular disorders
From pathophysiology to new treatments in epilepsy
Parkinson´s disease: advances in diagnosis and treatment
Critical issues on MS diagnosis and treatment
The congress programme includes interactive case presentations, 23 teaching courses,

16 workshops organised by the ENS subcommittees, practical breakfast sessions in clinical
neurophysiology and selected scientific sessions in the form of oral sessions, poster
sessions (guided poster walks) and satellite symposia.
Abstract Submission Deadline: February 11, 2009

Early Registration Deadline: April 22, 2009
For further information please contact:

ENS 2009, c/o AKM Congress Service
Association House, P.O. Box, CH-4002 Basel / Switzerland
Phone +41 61 686 77 77 Fax +41 61 686 77 88 Email info@akm.ch
www.ensinfo.org
ENS_Inserat_080306.indd 1 06.03.2008 15:33:26 Uhr
Events Diary
To list your event in this diary, email brief details to

Rachael Hansford at rachael@acnr.co.uk by 7 June, 2008
2008 June
MANAGEMENT OF May
2nd Migrating Course on Epilepsy
1-8 June, 2008; Trakai, Lithuania
E. Milda Endziniene endziniene@gmail.com or
13th European Congress of Clinical
“COLLAPSE?CAUSE” Neurophysiology
5-8 May, 2008; Istanbul, Turkey
Petra Novotny petra@epilepsy-academy.org
Signalling to Chromatin
www.eccn2008.org/ 4-8 June 2008; Cambridge, UK
Tuesday 24 June 2008 9th European Congress of Neuropathology http://firstcontact.hinxton.wellcome.ac.uk
8-10 May, 2008; Athens, Greece NEW
In the UK, “collapse?cause” is a common term in use in emergency departments in E. i.m.huang@amc.uva.nl Benign Paroxysmal Positional Vertigo
all hospitals. An abrupt loss of postural control is often, but not always, accompa- T. 30-2-107-257-693, F. 30-2-107-257-532 7 June, 2008; Chelmsford, UK
nied by transient loss of consciousness (T-LOC). Often, the first-responders and 6th Workshop of the International Society for E. info@physiouk.co.uk
subsequent clinical reviewers find no signs or symptoms, and many common tests Musculoskeletal and Neuronal Interactions
18th Meeting of the European Neurological
8-11 May, 2008; Cologne, Germany
are unhelpful. The clinical history, supplemented by an eye-witness account, is Society
E. info@mes-berlin.com Mrs Yvonne Beetz, 7-11 June, 2008; Nice, France
crucial, but a number of different causes of collapse and of T-LOC may look the T. 00 49-3-070-078-950 T. +41 61 686 77 11
same. This conference aims to try and steer clinicians towards a better understand- F. 49-3-07-007-895-111 F. +41 61 686 77 88
ing of causes and mechanisms, clarify terminology and the key points in clinical V Scientific Symposium of Polish Society for E. info@akm.ch
assessment and testing. Neurological Rehabilitation www.ensinfo.com
9-10 May, 2008; Tarnowskie Gory, Poland
Audience: Consultant physicians and doctors in training in emergency medicine, www.repty.pl NEW
Gross Motor Function Measurement Course
acute internal medicine, cardiovascular medicine, neurology, care of the elderly. In NEW (Bobath course)
addition, specialist nurses looking after patients in primary care will find this Matthew’s Friends Rainbow Ball 9 June, 2008; Derby, UK
conference useful. 10 May, 2008; Copthorne, West Sussex, UK T. 01332 254679
E. julie@matthewsfriends.org www.ncore.org.uk
This conference will be held at the T. 07748800438
6th International Society for Stem Cell
Royal College of Physicians, NEW Research Annual Meeting
11 St Andrews Place, Regent’s Park, London NW1 Health Care Records on Trial 11-14 June, 2008; Philadelphia, USA
13 May, 2008; Derby, UK E. isscr@isscr.org
Programmes and booking forms are available on-line at T. 01332 254679
www.ncore.org.uk NEW
www.rcplondon.ac.uk/conferences or from: Cervical Auscultation
Conference Department, Royal College of Physicians NEW
12 June, 2008; Derby, UK
Exploring Gait as it relates to Posture &
Tel: 020 7935 1174 Ext. 300/436/252 • Fax: 020 7224 0719 T. 01332 254679
Balance for Qualified staff
www.ncore.org.uk
Email: conferences@rcplondon.ac.uk 15 May, 2008; Derby, UK
T. 01332 254679 NEW
www.ncore.org.uk Kinetic Control: Diagnosis of Mechanical
AAC: Basic Principles & Practical Solutions Dysfunction & Stability of the Neck &
16 May, 2008; London, UK Shoulder Girdle
T. 0208 780 4500 x5140 13-16 June, 2008; Derby, UK
E. institute@rhn.org.uk T. 01332 254679
www.ncore.org.uk
1st Asian Oceania Conference of Physical and
Rehabilitation Medicine Genomics of Malaria Epidemiology
16-19 May, 2008; Nanjing, China 15-18 June, 2008; Cambridge, UK
Danny Yan http://firstcontact.hinxton.wellcome.ac.uk
T. 86 10 62 180 141 9th Eilat Conference on New Antiepileptic
F. 86 10 62 174 061 Drugs (EILAT IX)
E. info@aocprm2008.com 15-19 June, 2008; Sitges, Spain
Forthcoming Meetings 5th International Symposium on
Neuroprotection and Neurorepair:
F. +972 3 5175155
E. eilatix@targetconf.com
Cerebral Ischemia and Stroke www.eilat-aeds.com
17-20 May, 2008; Magdeburg, Germany
Diagnostic problems in the pain clinic NEW
T. +49(391)67-13088
Motivating the Unmotivated: helping difficult
Western Rooms, Liverpool Cathedral, Liverpool, E. georg.reiser@medizin.uni-magdeburg.de
patients
www.neurorepair-2008.de/
12 June 2008 BSRM Spring Meeting
17 June, 2008; Derby, UK
T. 01332 254679
19-20 May, 2008; Birmingham, UK www.ncore.org.uk
Every family matters: disability, pregnancy E. admin@bsrm.co.uk
T. 01992 638865 Study Day on MND
and parenthood The Royal Society of Medicine 17 June, 2008; Birmingham, UK
3rd National Neuroscience Nursing E. pam.aston@mndassociation.org
1 Wimpole Street, London, 19 June 2008 Conference: back to basics
20 May, 2008; London, UK NEW
E. annehaylock@markallengroup.com Clinical Trials in Neuromuscular Diseases
Managing poor performance in doctors - a tough 19-21 June, 2008; Freiburg, Germany
BISWG Annual General Meeting and Study
nut to crack The Royal Society of Medicine E. annette.pohl@uniklinik-freiburg.de
Day: ‘Money Matters 2’
www.treat-nmd.eu/assets/documents/
1 Wimpole Street, London, 9 July 2008 21 May, 2008; Birmingham, UK
workshop-schedule_draft.pdf
T/F. 0208 780 4530
E. psimonson@rhn.org.uk Cognitive Rehabilitation Workshop
Beyond pathways to work: health, work and Plasticity, Learning, and Development 20-21 June, 2008; London, UK
E. enquiries@braintreetraining.co.uk
well-being The Royal Society of Medicine 1 Wimpole 30-31 May, 2008; London, UK
www.braintreetraining.co.uk
E. rosalyn.lawrence@ucl.ac.uk
Street, London,10 September 2008 International Congress of Parkinson’s Disease
Brain Injury and the Law-Scotland Event
30 May, 2008; Dunfermline, UK and Movement Disorders
Chronic fatigue syndrome T. 0131 537 6857 22-26 June, 2008; Chicago, IL, USA
E. fenparry@blueyonder.co.uk/mhairi.mckay@ T. +1 414 2762145
UBHT Education Centre, Bristol, 18 September 2008 lpct.scot.nhs.uk E. info@movementdisorders.org
Magstim/ Institute of Cognitive Neuroscience NEW
Second TMS Summer School Management of “Collapse/Cause”
Call Chloe Waite on 020 7290 3844 30-31 May, 2008; London, UK 24 June, 2008; London, UK
T. 01994 240798 T. 020 7935 1174 Ext. 300/436/252
or book online www.rsm.ac.uk/events E. nick.lewis@magstim.com F. 020 7224 0719
www.magstim.com E. conferences@rcplondon.ac.uk

Events Diary
NEW Clinical Pharmacology and Pharmacotherapy 8th European Congress on Epilepsy

Vocational Rehabilitation September, 2008; ILAE–VIREPA 21-25 September, 2008; Berlin, Germany
October
30 June, 2008; Cambridgeshire, UK distance learning course E. berlin@epilepsycongress.org AANEM Annual Scientific Meetings
T. 01353 652176 E. office@epilepsy-academy.org www.epilepsyberlin2008.org 7-10 October, 2009; San Diego, California, USA
F. 01353 652164 www.epilepsy–academy.org T. + (507) 288-0100
www.neuropage.nhs.uk NEW
F. + (507) 288-1225
www.ozc.nhs.uk NEW 10th National Conference - Parkinson’s
E. aanem@aanem.org
Federation of the European Societies of Disease: responding to mental health issues in
Neuropsychology parkinson’s 19th World Congress of Neurology
July 2-5 September, 2008; Edinburgh, UK 23 September, 2008; Birmingham, UK 24-30 October, 2009; Bangkok, Thailand
T. 01332 254679 MA Healthcare Ltd www.wcn2009bangkok.com
Fourth International Neuroacanthocytosis www.ncore.org.uk T. 01722 716007
Symposium: Bridging clinical and basic aspects
1-2 July, 2008; London/Oxford, UK Genomic Perspectives to Host Pathogen
F. 0207 733 8174
www.mahealthcareevents.co.uk
2010
E. glenn@naadvocacy.org Interactions
T. 020 7937 2938 3-6 September, 2008; Cambridge, UK 18th Ion Channel Meeting April
http://firstcontact.hinxton.wellcome.ac.uk 23-26 September, 2007;
SRR Summer Meeting Presqu ile de Giens, France 62nd Annual Meeting of the American
Making the Evidence Work for your Patients
2-3 July, 2008; Preston, UK E. arnaud.monteil@igf.cnrs.fr Academy of Neurology
and their Families
www.srr.org.uk http://congres.igh.cnrs.fr/canaux-ioniques/ 10-17 April, 2010; Toronto, Canada
4-5 September, 2008; Southampton, UK
E. dforshaw@uclan.ac.uk www.aan.com
T. +44 (023) 8079 8669 5th World Congress for NeuroRehabilitation
F. +44 (023) 8079 4340 24-27 September, 2008; Rio de Janeiro, Brazil
Inflammatory Neuropathy Consortium (INC)
E. neurorehab2008@soton.ac.uk E: traceymole@wfnr.co.uk
September
Meeting of the Peripheral Nerve Society (PNS)
4-5 July, 2008; Paris, France www.neurorehab2008.soton.ac.uk www.sarah.br/wfnr-rio2008 Congress of Neurological Surgeons Annual
http://pns.ucsd.edu/INC.htm Meeting
NEW 6th World Stroke Congress
European Headache and Migraine Trust 16-21 September, 2010; San Francisco, USA
ILAE UK Chapter Annual Scientific Meeting 24-27 September, 2008; Vienna, Austria
International Congress 2008 Congress of Neurological Surgeons
9-11 July, 2008; Dundee, UK E: stroke2008@kenes.com
4-7 September 2008, London, UK T. +847 240 2500
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Techniques & Applications of Molecular Understanding Neuroscience: an innovative October
Biology approach for mental health practitioners October
8-9 September, 2008; London, UK AANEM Annual Scientific Meetings
14-17 July, 2008; Coventry, UK
E. annehaylock@markallengroup.com EPDA Euroyapmeet Conference 6-9 October, 2010; Quebec City, Quebec, Canada
T. 024 7652 3540
3-5 October, 2008; Zagreb, Croatia T. + (507) 288-0100
E. Charlotte.Moonan@warwick.ac.uk BSS hosting the 19th Congress of the European
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Parkinson’s Academy/PD Section, British
9-13 September, 2008; Glasgow Advanced Cognitive Rehabilitation Workshop:
Geriatrics Society Specialist Registrar
E. enquiries@sleeping.org.uk Attention and Information Processing
Masterclass
10-11 October, 2008; Ljubljana, Slovenia 2011
28 July-1 August, 2008; Truro, Cornwall ABN Autumn Scientific Meeting
E. ursa.cizman@ir-rs.si
E. Red Publishing Ltd 10-12 September, 2008; Aviemore, UK
redoffice@btinternet.com E. Karen.reeves@theabn.org Mental Dysfunctions in Parkinson’s Disease April
16-19 October, 2008; Dresden, Germany 63rd Annual Meeting of the American Academy
Genome Informatics
T. +41 22 908 0488 of Neurology
August 10-14 September, 2008; Cambridge, UK
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NEW
VIIIth Congress of the EANO www.kenes.com/pdment2008
Biologising Pain with Lorimer Moseley
12 August, 2008; Nottingham, UK
12-14 September, 2008; Barcelona, Spain
NEW September
T. +43 1 4051383 0
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Neurology (CONy)
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23-26 October, 2008; Athens, Greece
Congress on Pain California, USA
Evolution of Brain, Behaviour & Intelligence www.comtecmed.com/cony
13-15 August, 2008; London, UK T. + (507) 288-0100
12-14 September, 2007; Hinxton, UK E. cony@comtecmed.com
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12th World Congress on Pain E. wtmeetings@wtconference.org.uk November
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17-22 August, 2008; Glasgow, UK
International Symposium on ALS/MND October
T. 001 206 547 6409 NEW
E. iaspdesk@iasp-pain.org 3-5 November, 2008; Birmingham, UK Congress of Neurological Surgeons Annual
‘Mind in the Brain’ (a Festschrift in honour of E. pam.aston@mndassociation.org
Professor Chris Frith, FRS) Meeting
12th European Federation of Neurological 1-6 October, 2011; Washington D C, USA.
17-18 September, 2008; London, UK Advanced Cognitive Rehabilitation Workshop
Societies Congress Congress of Neurological Surgeons
E. Rosalyn Lawrence rosalyn.lawrence@ucl.ac.uk 21-22 November, 2008; London, UK
23-26 August, 2008; Madrid, Spain T. +847 240 2500
E. enquiries@braintreetraining.co.uk
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Island, USA NEW www.neurosurgeon.org
Interactome Networks
T. + (507) 288 0100 Benign Paroxysmal Positional Vertigo
27-30 August, 2008; Cambridge, UK
http://firstcontact.hinxton.wellcome.ac.uk
F. + (507) 288-1225
E. aanem@aanem.org
22 November, 2008; Reading, UK
E: info@physiouk.co.uk
2012
2nd Baltic Sea Summer School on Epilepsy
31 August-1 September, 2008; Denmark
7th Mediterranean Congress of Physical
Medicine & Rehabilitation Medicine 2009 September
E. petra@epilepsy-academy.org. 18-21 September, 2008; Potorose, Slovenia Congress of Neurological Surgeons Annual
E. marincek.crt@mail.ir-rs.si February Meeting
29 September-4 October, 2012;
September Understanding and Dealing with Behaviour 37th Annual INS Meeting San Francisco, USA.
Problems 11-14 February, 2009; Atlanta, Georgia, USA Congress of Neurological Surgeons
Genetics of Epilepsy 19-20 September, 2008; London, UK International Neuropsychological Society T. +847 240 2500, F. +847 240 0804
September, 2008; E. enquiries@braintreetraining.co.uk T. + (614) 263-4200 E. info@1CNS.org
ILAE–VIREPA distance learning course W. www.braintreetraining.co.uk F. + (614) 263-4366 www.neurosurgeon.org
E. office@epilepsy-academy.org,
Congress of Neurological Surgeons Annual E. ins@osu.edu
www.epilepsy–academy.org
EEG in the diagnosis and management of

Meeting
20-25 September, 2008; Orlando, USA April 2013
epilepsy Congress of Neurological Surgeons
September, 2008; ILAE–VIREPA T. +847 240 2500 61st Annual Meeting of the American Academy October
distance learning course F. +847 240 0804 of Neurology
E. office@epilepsy-academy.org E. info@1CNS.org 25 April- 2 May, 2009; Seattle, WA, USA Congress of Neurological Surgeons Annual
www.epilepsy–academy.org www.neurosurgeon.org www.aan.com Meeting
19-24 October, 2013; San Francisco, USA
Neuroimaging 10th International Symposium On May Congress of Neurological Surgeons
September, 2008; ILAE–VIREPA Thrombolysis And Acute Stroke Therapy T. +847 240 2500
distance learning course 21-23 September, 2008; Budapest, Hungary 5th ISPRM World Congress F. +847 240 0804
E. office@epilepsy-academy.org E. tast2008@kenes.com 9-13 May, 2009; Istanbul, Turkey E. info@1CNS.org
www.epilepsy–academy.org www.kenes.com/tast2008 E: traceymole@wfnr.co.uk www.neurosurgeon.org

Conference Report
The Muscular Dystrophies

A meeting organised by the Medical Genetics Section of the Royal Society
of Medicine
19 November, 2007; London, UK.
I
nclement weather and London’s notorious and abnormal glycosylation (associated to-date achieved by the synthesis of accurate clinical
public transport system did not deter over with mutations in six separate genes) results in data, muscle biopsy findings and selected
100 clinicians and scientists from attending conditions such as Walker Warburg syndrome, genetic studies, and the need for close collabo-
this meeting. The morning sessions were Fukuyama muscular dystrophy and muscle eye ration with national centres of expertise (such
chaired by Lord Walton of Detchant, an brain disease. Whilst initially good correlation as Professor Bushby’s) was readily apparent.
inspired choice given his personal contribution between specific gene mutations and clinical The afternoon session began with another
in this field, including (the audience was syndromes was suspected, Professor Muntoni’s authority in his field, Professor Padberg
reminded) the first description of Duchenne group has demonstrated that each of the six (Nijmegen) talking on fascioscapulohumeral
muscular dystrophy (DMD) in an individual genes can result in a highly variable phenotype, muscular dystrophy (FSHD). This autosomal
with Turner’s syndrome. He excused himself including (confusingly) adult-onset limb-girdle dominant disorder is the third most common
from the afternoon session, as he was speaking muscular dystrophy (for example FKRP). muscular dystrophy (after myotonic dystrophy
at the House of Lords on the Human In a commendably clinically orientated talk, and DMD/BMD), but more than 30% of gene
Fertilisation and Embryology Bill – a reflection Dr David Hilton-Jones (Oxford) covered carriers (females more than males) may be
of the rapid expansion of knowledge and tech- Duchenne and Becker muscular dystrophies. asymptomatic. (Age of onset is older in females
nologies in Medical Genetics, and the conse- Controversially he said that an Italian, Conte, too.) There is often asymmetrical and frequent-
quent ethical and legal ramifications. Indeed should be credited with the first description of ly unrecognised facial weakness first. At clinical
the ethical considerations surrounding the DMD in 1836, preceding even Meryon. This presentation, however, shoulder-girdle weak-
diagnosis and management of these disorders was firmly rebutted by Professor Emery at the ness is common (80%), while foot extensor
were highlighted by Professor Alan Emery end of Dr Hilton-Jones’ talk, who maintained (10%), pelvic-girdle (5%) and facial muscle
(Oxford), the organiser of the meeting who also that the true credit should go to Meryon, as the (5%) weakness are less so. Disease progression
kicked off the talks. He talked movingly of the latter’s description in 1851 not only preceded slows in the sixth decade, but at 60 years two-
sometimes tragic implications of establishing Duchenne’s but it included the key observa- thirds have foot extensor weakness, half have
these diagnoses to patients and families. tions that it was maternally inherited and was pelvic-girdle weakness and 20% are wheelchair
Professor Emery gave an overview of the explo- primarily a disorder of muscle. DMD and dependent outdoors. Coats’ disease, a retinal
sion of knowledge there had been in the two Becker muscular dystrophy (BMD) are allelic vasculopathy (often subclinical), can be pres-
decades since the discovery of dystrophin. disorders, and whilst ‘out-of-frame’ mutations ent, and hearing loss and epilepsy have been
Currently, there are 40 or so genes associated resulting in truncated dystrophin cause DMD, described. Professor Padberg next considered
with the muscular dystrophies, encoding pro- ‘in-frame’ mutations cause BMD. Clinical the molecular genetic basis of FSHD. It is asso-
teins many of which are now known to inter- ‘gems’ to take away included the observation ciated with a reduction in the number of 3.3 kb
link. He pointed out that questions remained, that any boy with delayed motor, speech or gen- repeats (normally more than 11) in the D4Z4
including the explanations for phenotypic het- eral intellectual development should have his locus on 4q35. Whether a transcript (DUX4) or
erogeneity associated with single genes (or even creatine kinase (CK) measured. Management an effect on an upstream gene (FRG1) mediates
single mutations) and allelic heterogeneity with (non-invasive) ventilatory support can disease is a matter of debate, but epigenetic
(where mutations in different genes result in an enable survival into the third and fourth mechanisms including hypomethylation of the
identical clinical phenotype). He talked also of decades. The use of drugs to manage cardiomy- repeat unit seem to be implicated in the patho-
the possible interactions of particular environ- opathy and corticosteroids to prolong survival physiology.
mental agents (especially pathogens) with spe- were mentioned. Clinical features associated Professor Glen Morris (Oswestry) next
cific proteins involved in certain muscular dys- with the milder BMD include exercise-induced talked about Emery-Dreifuss muscular dystro-
trophies. He left the audience with the salutary cramp (resembling McArdle’s disease) and phy (EDMD), which is caused by mutations
reminder of the dangers of following dogma asymmetric calf hypertrophy. It can be difficult affecting the genes encoding emerin (X-linked),
(for example the current view that abnormal to discriminate BMD from spinal muscular lamin A/C, or the nesprins. Crucially, all three
genes equal disease) in attempting to overcome atrophy, and 10% of subjects are wheelchair- proteins are co-located in the nuclear mem-
any challenge, citing the explosion of the bound by 40 years. Cardiomyopathy again brane. Clinically EDMD is characterised by
Hindenburg in 1937 and the subsequent aban- requires monitoring and treatment. Finally, Dr early contractures (Achilles tendons, elbows
donment of airships - which up to that time Hilton-Jones covered the specific issues of and neck), muscle wasting and weakness initial-
had been the preferred means of transatlantic manifesting carriers (associated with non-ran- ly in proximal upper limbs and distal lower
air travel. dom X inactivation), and the disorders associ- limbs, and cardiac conduction defects. The
Professor Francesco Muntoni (London) in a ated with point mutations in dystrophin rang- importance of the insertion of cardiac pace-
scintillating talk described the congenital mus- ing from muscle pain and cramps without makers and defibrillators in management was
cular dystrophies (CMDs), which generally weakness to isolated cardiomyopathy and iso- stressed. Lamin A/C mutations (associated with
present before six months of age. It was inter- lated ‘hyperCKaemia’. dominant EDMD) can cause dilated cardiomy-
esting to note the extent of central nervous sys- Professor Kate Bushby (Newcastle) talked on opathy necessitating cardiac transplantation,
tem involvement in some forms, reflecting the limb-girdle muscular dystrophies (LGMD). and provides a further example of phenotypic
expression of some proteins in the brain during Autosomal dominant and recessive forms exist, heterogeneity- being associated with a form of
development. He highlighted three disorders. and whilst clinically (and genetically) heteroge- CMD and one type of LGMD, both complicat-
Ullrich variant and merosin deficient CMD are neous all share a predominant pattern of prox- ed by cardiac disorders too.
associated with deficiency of two extracellular imal myopathy. It was explained that determin- Professor Bjarne Udd (Tampere) covered the
matrix proteins (collagen VI and laminin α2 ing the exact type (if possible) was important confusing area of the distal muscular dystro-
respectively), and are phenotypically reason- for genetic counselling and determining prog- phies. Once again, rapid growth in knowledge
ably distinct. Glycosylation of alpha dystrogly- nosis, as different forms were associated with has taken place and more than 16 genetically
can, a peripheral membrane protein, enables it variable involvement of the cardiac and respira- distinct types are now recognised. About half
to interact with extracellular matrix proteins, tory systems. The exact diagnosis could only be cause distal disease exclusively, whilst the other

Conference Report
half can be associated with scapuloperoneal, apeutic interventions in DM1. the field (with only a few exceptions, such as
proximal or generalised phenotypes. Most of In the last part of the meeting, Professor Kay oculopharyngeal muscular dystrophy) had
these genes appear to encode sarcomeric pro- Davies (Oxford) and Dr Jennifer Morgan been comprehensively covered. Neurologists in
teins, as do the recently identified genes associ- (London) tackled the treatment of DMD, training, especially those with an interest in the
ated with distal arthrogryposis (which is prob- addressing gene and stem cell therapies respec- genetic aspects of disease are encouraged to join
ably a manifestation of congenital distal tively. There seem to be numerous (some very the Medical Genetics Section of the RSM,
myopathy). The highly selective nature of mus- ingenious) interventions capable of correcting which is one of its youngest Sections and, on
cle involvement is striking, and is even better or ameliorating the absence of dystrophin, and the evidence of this meeting, also one of its
appreciated by magnetic resonance studies. it may be that a combination of approaches will most dynamic.
Finally, in this section, Dr Gurman Pall need to be utilised eventually. It was heartening I am grateful to Professor Emery for review-
(Glasgow) spoke on myotonic dystrophy to note the phase I/II trials in planning or ing the manuscript.
(DM1). He explained that the triplet-repeat progress, and Professor Davies’ view that there
expansion characteristic of the disease pro- was “great promise…(for the successful treat- Rajith de Silva, Department of Neurology,
duced mRNA containing expanded CUG ment of DMD)…in the next decade”. Queen’s Hospital, Romford, Essex, UK.
repeats which are ‘toxic’ to cells. Dr Pall and col- All in all, this was an outstanding meeting,
leagues have identified short (CUG)n-RNA bringing together a faculty of true opinion
References
fragments in cells expressing mRNA containing leaders in their respective specialities. For work-
1. Barnes PRJ & Hilton-Jones (eds.). (2003) Myopathies in
expansions characteristic of DM1, which may ers in the field there were unrivalled opportuni- clinical practice. London & New York: Martin Dunitz.
represent an intermediate degradation product ties for networking and sharing recent knowl- 2. Emery AEH & Muntoni F. (2003) Duchenne muscular
of the ‘toxic’ repeat-containing transcripts. edge behind the scenes, and in this regard it dystrophy. 3rd ed. Oxford: Oxford University Press.
Characterisation of this potential decay path- resembled an international symposium. I found 3. Winder SJ (ed.) (2006) Molecular mechanisms of muscu-
way may obviously yield opportunities for ther- it of enormous educational value, and felt that lar dystrophies. Georgetown, TX: Landes Bioscience.
Society for Research and Rehabilitation

Winter Meeting 2008
15 January, 2008; Oxford, UK.
T
he SRR Winter conference was held on
the 15th January 2008 at Oxford Brookes
University, hosted by Dr Helen Dawes.
Despite only being a one day conference there
was a wide range of material presented: free
research papers, poster presentations, work in
process posters and three symposia. The day’s
proceedings were started by Professor Paul
Matthews’ interesting symposium on the utility
of different brain imaging techniques to explore
the relationship between brain plasticity and
rehabilitation.
After a quick coffee and the first chance to
view the posters, Professor Cath Sackley gave
the first of her presentations on a cluster ran- During the coffee break delegates had their during cognitive tasks.
domised controlled trial of physiotherapy and final chance to view both the posters presenta- The day concluded with final free research
occupational therapy intervention to enhance tions and the work in progress posters: Poster presentations. Dr John Saxton presented his
mobility and activity in care home residents. presentations included: lower limb muscle weak- work on the physiological responses to tread-
The first session also included a qualitative ness in Huntington’s disease by Dr Monica mill walking with Nordic poles in patients with
paper examining experiences of an Exercise Busse; walking and wheelchair navigation in intermittent claudication, Mr Atzori his study
Referral Scheme from the perspective of people stroke patients with left sided visual neglect by of concurrent validity of the IDEEA activity
with chronic stroke presented by Helen Mrs Kelly O'Leary; the ‘Dark Art’ of physiother- monitor to quantify mobility related activities
Sharma, a randomised single blind trial of the apy: experiences of people with cerebellar ataxia among people with stroke in free-living condi-
use of multi-sensory stimulation to improve by Elizabeth Cassidy; modulating performance tions, Dr Eimear Smith on examination of the
functional performance in older people with on wheelchair navigation in patients with unilat- prevalence of low bone mineral density in
dementia, by Dr Lesley Collier, and a survey of eral neglect following stroke by Dr David Punt; patients at a national rehabilitation centre and
the circumstances surrounding falls among self-optimisation of walking speed following we finished where we started with Dr Cath
people with Parkinson’s disease by Professor stroke by Dr Johnny Collett; modeling recovery Sackley talking about a phase II randomised
Ann Ashburn. after stroke, Ms Shweta Malhotra; can botu- controlled trial of bilateral limb movement
Following lunch, Professor Derick Wade gave linum toxin, administered in the early stages fol- exercise in chronic hemiparetic stroke patients.
a thought-provoking symposium exploring lowing a stroke help the recovery of arm func- Many thanks to all the presenters and dele-
how, paradoxically, rehabilitation may prolong tion; estimating effect size from a phase II pilot gates for an interesting, informative and
disability and illness behaviours, which gener- study by Ms Elizabeth Cousins. Work in progress thought-provoking day. The Summer Meeting
ated an interesting discussion. This was fol- posters included: examining outcome measures will be held in Preston, hosted by Professor
lowed by an interesting and entertaining sym- of inpatient care in profound brain injury; eco- Caroline Watkins of the University of Central
posium by Dr Tom Manly on how investigating nomic analysis of return to work after traumatic Lancashire.
variability within impairment measures can be brain injury; reintegration outcomes following
utilised in rehabilitation for examining atten- spinal cord injury; and the feasibility of NIRS in Dr Helen Dawes,
tion and executive function. detecting neural activation in the DLP cortex Oxford Brookes University, Oxford UK.

Conference Report
The Parkinson’s Disease Non-Motor Group 3rd Annual Meeting

8 March, 2008; London, UK.
T
he Parkinson’s Disease Non- agement and exercise. For more severe
Motor Group (PDNMG) 3rd depression, he suggested SSRIs, but called
annual meeting was held at the for more research into PD and depression
Royal Society of Medicine, London, on since there is currently no established
8th March 2008 and was attended by treatment algorithm. Ongoing trials sug-
170 health care professionals. It provid- gest the use of combined serotonin-nora-
ed an opportunity to review the past drenaline therapies such as venlafaxine
year’s progress in the field of non- and D2/D3 agonists such as pramipexole,
motor symptoms (NMS) and another for patients with treatment resistant
informative and invaluable day of depression with PD. However all have
learning. limited evidence of safety and tolerability,
Attendees were welcomed by PDNMG and cognitive behavioural therapy may
Chairman, K Ray Chaudhuri, who briefly therefore also have an important role.
discussed the prevalence of non-motor Mrs J Johnson (London), a clinical spe-
symptoms (NMS) including dribbling saliva, limbic dopamine dysfunction. cialist speech and language therapist in progres-
constipation, depression, sleep disorders, apathy, The afternoon session began with a presenta- sive neurological disorders, outlined the main
hallucinations and dementia which complicates tion by Professor P Barone (Milan) on the epi- motor features of dysarthria. She reviewed the
the lives of people with Parkinson’s disease (PD). demiology, treatment and management of hallu- drug treatments, therapeutic devices and the
Professor E Tolosa (Barcelona) described the pre- cinations. He highlighted the facts that atypical management programmes (including the Lee
clinical phase of PD. He examined the correlation anti-psychotics were recommended, long term Silverman Voice Treatment) available to patients.
between Braak staging with clinical manifesta- treatment is the rule, patients with concomitant Mrs Johnson concluded by calling attention to
tions, imaging of the substantia nigra, and non- dementia with visual hallucinations should prob- the paucity of drug trials that use speech assess-
motor symptoms including olfactory distur- ably start a cholinesterase inhibitor, and that test- ment as end points.
bances, depression and autonomic system disor- ing cognitive function is an essential part of the Professor P Odin (Bremerhaven) discussed
ders. Professor Tolosa suggested that NMS are clinical examination. sexual dysfunction and highlighted previous
not prodromal but in fact part of PD. Professor A Professor C Clarke (Birmingham) offered an studies which showed that 68.5% of patients
Schapira (London) then delivered a talk on when appraisal of drug therapy for motor and non- with PD suffered from such problems, com-
to start treatment for PD. He discussed the ‘pre- motor symptoms. He summarised the short- pared to 33% in a healthy group of the same
clinical’ markers including depression and olfac- falls of previous trials in symptomatic early PD mean age. While a combination of autonomic
tory disturbances, the pathological clues, neu- treatment and then introduced the ongoing dysfunction and psychological anxiety was
roimaging assessment of progression, and genet- PDMED trial, which looks at both the patient- blamed for hyposexuality, Professor Odin rec-
ic linkages. He highlighted results from the related quality of life and health economics. He ommended the involvement of gynaecological
DATATOP, TEMPO and QE2 studies. Professor then discussed the surgical options for PD and urological teams, psychosocial counselling,
Schapira reviewed the advantages of early including bilateral subthalamic stimulation. anti-anxiety medication, the use of sildenafil
monotherapy, the issue of neuroprotection and Finally, he discussed the future of drug therapy and related agents, and a reduction in PD med-
the conflicting evidence surrounding the con- in PD, including prolonged release ropinirole, ication (if possible).
cept. He concluded that the eventual decision to safinamide, and antidyskinesia agents such as Dr G MacPhee (Glasgow) discussed gambling,
treat early must be made after a patient orientat- istradefylline, an adenosine A2a receptor antag- impulsive and compulsive behaviour, outlining
ed discussion, balancing the side effects of treat- onist. the progression from ‘recreational’, ‘problem’ and
ment with the reported improvements in quality Professor F Stocchi (Rome) discussed the ‘pathological’ gambling (PG), drawing parallels
of life, symptom control and disease progression. management of respiratory dysfunction and with obsessive compulsive disorder. Dr MacPhee
Professor D Burn (Newcastle) then examined sleep problems in PD. He reported the early ended with a review of management. Whilst the
the similarities and differences between dementia results of his own study in 30 patients (all non- evidence base remains poor, an individualised
with Lewy bodies (DLB) with PD dementia smokers) with respiratory dysfunction and PD. approach utilising neuroleptics, mood stabilisers
(PDD), and discussed diagnostic criteria, man- Assessments of maximal inspiratory pressure, and psychological counselling, including CBT
agement algorithms and drug treatments for pulmonary function tests and dyspnoea percep- and Gambler’s Anonymous, was advised.
PDD. He briefly reviewed cholinesterase tion in patients in ‘on’ and ‘off’ phases showed Dr M Visser (Netherlands) discussed quality of
inhibitors, and memantine as possible therapies, that 90% of patients had difficulties when ‘off’ life determinants in PD. Sexual, urinary, gas-
then proceeded to talk about drugs with multiple compared to 78% when ‘on’. He postulated that trointestinal and thermoregulatory problems
modes of action (including ladostigil and adeno- the results can be explained by bradykinesia of appear to be most predictive of low Health
sine receptor antagonists). Finally, various anti- the diaphragm and intercostal muscles, and pos- Related Quality of Life scores. Dr Visser suggest-
amyloid strategies for PDD, such as statins, mus- tural problems. He then went on to review sleep ed that future treatment should target improve-
carinic-M1 receptor agonists, anti-inflammatory problems which are highly prevalent in PD, and ment in activities of daily living, psychosocial
agents and amyloid immunisation therapy were their effect on quality of life. He suggested treat- problems such as depression, and the autonomic
discussed. ments for nocturnal akinesia, rigidity and dysto- nervous system.
Professor D Brooks (London) outlined the nia (prolonged release levodopa and COMT-I), The valuable questions which followed many
uses of FDG-PET, FP-SPECT, F-Dopa PET, sleep initiation problems (benzodiazepines) and of the presentations made a significant contribu-
Acetylcholinesterase Imaging and PET amyloid sleep maintenance problems (amitriptyline, tion to the proceedings and ensured that lively
plaque imaging in PDD, DLB and Alzheimer’s clonazepam and clozapine). discussion continued in-between sessions. A
disease. PDD patients demonstrated decreased Professor R Brown (London) emphasised the fourth meeting is already at an advanced stage of
parieto-temporal metabolism levels, decreased importance of screening and detection of symp- planning.
mesocortical dopamine levels and globally toms such as depression which are frequently
decreased acetylcholinesterase levels. Professor stigmatised, and mentioned the various assess- Kartik Logishetty, Sharon Muzerengi
Brooks talked briefly on depression and conclud- ment tools for measuring these symptoms. For and K Ray Chaudhuri,
ed that depressed PD patients were more likely to mild depression, he recommended anti-depres- King’s College Hospital,
demonstrate frontal lobe hypometabolism and sants and general measures such as anxiety man- Denmark Hill, London, UK.

Conference Report
The MS Society Convention for People with MS – MS Life 2008

29-30 March, 2008; Manchester, UK.
M
S Life 2008 was held in Manchester
and was Europe’s biggest ever event
for the MS community. The conven-
tion was a massive achievement, attended by
more than 3,500 people touched by multiple
sclerosis, including over 350 wheelchair users
and 450 visitors with mobility aids.
Every part of the UK was represented and
there were many European and international
visitors who were drawn to the event by the
research presentations, workshops and over 80
exhibition stands aimed at offering information
on improvements in quality of life for people
affected by MS. Highlights of the weekend also
included live cookery demonstrations, Kinky
Myelinky – the exclusively inclusive club night
and the My Style fashion show featuring mod-
els from the MS community in front of a sell
out crowd of 400.
In response to delegate feedback from pre-
vious years the research sections of the con-
vention were expanded and improved. The two MS Society funded centres, The Cambridge
Meet the Scientist zone, where delegates could Centre for Myelin Repair and the Edinburgh
link up with research scientists to gain an Translational Research Centre, would address
insight into basic laboratory projects in the the issues of prevention of nerve fibre loss,
field of MS, was developed to become the which causes chronic progressive disease and
Meet the Expert zone. As well as scientists, the promotion of myelin repair using new tech-
there was representation from many parts of nologies such as stem or precursor cell reactiva-
the multi-disciplinary team involved in the tion or transplantation in the search for new
care of a person with MS, including MS nurs- therapies for MS.
es, clinicians and clinical psychologists. The Prof David Bates, a clinical neurologist at the
zone also boasted information stands focus- University of Newcastle upon Tyne followed
ing on magnetic resonance imaging (MRI) recovery to take place. with a discussion on the future of disease mod-
and the UK MS Tissue bank. Dr Brenda Banwell, Director of the ifying therapy. He focused on potential thera-
In parallel with around 30 workshops on var- Paediatric Multiple Sclerosis Clinic in Toronto, pies which are currently in phase III trials,
ied topics including social care, living with pri- Canada, discussed why MS is increasingly being assessing their effectiveness in treating MS. He
mary progressive MS, managing fatigue, care recognised in children and showed why the also touched on key contemporary issues, ques-
services and starting a family, seven interna- diagnosis of MS in a child or teen may be com- tioning how to treat those for whom tradition-
tional research speakers gave talks on a diverse plicated and delayed. Dr Banwell’s talk high- al MS therapies are not effective and future pos-
range of topical subject areas in the field of MS lighted the fact that research into the causes of sibilities for treating MS progression.
throughout the two day conference. Dr Alasdair MS may be particularly important in the The research talks, one of the most popular
Coles, an academic neurologist in Cambridge youngest people diagnosed with the condition elements of the MS Life weekend, ended with a
working on experimental therapies for MS, because environmental triggers may be more fascinating presentation from Prof Carolyn
began the sessions with a discussion of risks, readily detected in people closer to the onset of Young, who heads a Neurological
placebos and myth busting. He presented some the condition. Dr Banwell also focused on the Rehabilitation Unit at the Walton Centre in
of the trends and conclusions which can be impact of MS on the lives and activities of chil- Liverpool. Prof Young’s talk, entitled ‘If I had
drawn from looking at longitudinal data from dren and teens. MS…’, covered topics such as exercise, diet,
people with MS and discussed the balance Saturday closed with an open debate chaired medication, stress and rehabilitation for people
which needs to be achieved between potential by broadcaster Nicholas Owen which explored with MS. She gave expert advice on the best way
benefits and risks associated with treatment of the issue of patient choice. A panel comprising to make the most of clinical consultations and
a long term condition such as MS. He also MS Society Chief Executive, Simon Gillespie, MS teams as well as information on how trials
reviewed data on the effectiveness of current people with MS, a representative of MS are run and her views on the benefits of partic-
therapies for MS and discussed the need for Therapy Centres and a neurologist hosted a ipation in research.
open and candid information to be provided lively discussion on many topics including new The conference was an excellent opportunity
on the benefits of these treatments. MS treatments and how best to balance the for people affected by MS to hear about the lat-
Prof David Miller, Head of the Department benefits against harmful side effects. est advances in research and provided the
of Neuroinflammation at the Institute of Prof George Ebers, a clinician at the opportunity for people from every area of the
Neurology followed this with an update on Wellcome Trust Centre for Human Genetics, MS community to share experiences and their
research using MRI methods to improve diag- opened the research presentations on Sunday ideas about the many aspects of living with MS.
nosis, identify prognostic markers, understand with a talk on genetics in MS and the inheri- Interviews with the scientists and a full confer-
disease mechanisms and monitor new treat- tance of MS susceptibility. He summarised his ence breakdown are available on the MS Society
ments in MS. He showed how a new and more work investigating the genetic epidemiology of website.
powerful generation of MRI scanners is now MS as well as his primary interest in studying
being manufactured which are able to detect gene environment interactions in MS. Dr Laura Bell,
the damage to nerve fibres that causes disabili- The audience then heard from Prof Charles Research Communications Officer,
ty as well as the repair of myelin that enables ffrench-Constant, whose session described how Multiple Sclerosis Society.

Conference Report
British Neuro-Oncology Society (BNOS)

PREVIEW:
Annual Conference 2008

25-27 June, 2008; Lancashire, UK
T
he University of Central Lancashire nary and consist of short presentations and
together with the Lancashire NHS posters in addition to key note addresses.
Trust Royal Preston Hospital are host- This year the conference is pleased to
ing this years BNOS conference from June include talks from Professors Vescovi
25th to the 27th. BNOS is the modern devel- (Milan, Italy) and Lamzus (Hamburg,
opment of the British Neuro Oncology Germany) upon the involvement of stem
Group, formed in 1980, and includes UK cells in brain tumour and Professors Burnet
leaders in basic science research together (Cambridge) and Stummer (Dusseldorf,
with a clinical membership drawn from Germany) on novel advances in radiothera-
consultant neuropathlogists, neurosur- py and neurosurgery. BNOS actively collab-
geons, oncologists, nurses and other health orates with the UK brain tumour charities
professionals who all have a common inter- and with the IBTA (International Brain
est in malignant CNS tumours in both Tumour Alliance) who have generously
adults and children. given their financial support towards host-
The conference venue will be in the ing these eminent speakers.
Darwin and Foster buildings at the centre of Peer reviewed abstracts, including
the University campus a few hundred yards extended short papers from the main
Charles Davis,
from Preston city centre. Accommodation speakers, will be published in the British Consultant
will be at the nearby Holiday Inn and Travel Journal of Neurosurgery. Copies of the edi- Neurosurgeon, RPH,
Lodge. Preston is well served for transport tion, which will have a particular emphasis Vice-president of BNOS
routes and there is a direct rail link with on brain tumour, will be available for dele- and Co-organiser
BNOS2008.
Manchester International Airport. gates at the conference.
This year it is estimated that the confer- A full social programme is planned which
ence will attract approximately 280 dele- includes a reception evening with the mayor
gates, and as well as the scientific sessions, of Preston in attendance at the Harris
will also include an extensive trade exhibi- Museum, a stunning Grade I listed neo-clas-
tion, ‘education afternoon’ and postgradu- sical building and the conference banquet at
ate forum. Consistent with the Society’s the National Football Museum, one of the
original aims of promoting a dialogue on UKs most original venues, with the oppor-
the management and biology of primary tunity for interactive participation and
malignant brain tumours between basic cabaret entertainment. Further details and
scientists and clinicians, the meetings are appropriate registration and abstract sub-
kept as informal as possible. mission forms may be found on the website:
Scientific sessions will be inter-discipli- www.uclan.ac.uk//bnos2008 The Darwin Lecture Theatre. UCLan.
PREVIEW: ABN Meeting

10-12 September, 2008; Aviemore, UK
W
here better to enjoy a bracing academic programme than the a highland dinner and ceilidh. The ideal way to travel if you are coming
Scottish Highlands in the early Autumn? The conference will be from or through London is on the sleeper to Aviemore from Euston. There
held at the Hilton Coylumbridge which has ample on-site are potentially 36 first class single berths, and up to 84 places in standard
accommodation (http://www.hilton.co.uk/coylumbridge), and is sur- class double berths, which can be booked 12 weeks in advance of the date
rounded by the beauty of the Cairngorms National Park. Why not stay on of travel. You can fly to Inverness (we will lay on coaches) from most UK
for the weekend, and bring your partner or family, to enjoy a wild adven- airports. Deadline for abstracts will be the end of May 2008 (tbc).
ture or two around Aviemore? You can choose from archery, gorge walk-
ing (or swimming, if you're brave), canoeing, hill walking, sled dog tours, Rustam Al-Shahi Salman, MA PhD FRCP Edin,
fishing, mountain biking, pony trekking, or even golf. See MRC clinician scientist and honorary consultant neurologist,
http://www.visitaviemore.com and http://www.rothiemurchus.net for Bramwell Dott Building,
more details. Department of Clinical Neurosciences,
As well as the usual scientific presentations, case reports and the tradi- Western General Hospital, Edinburgh, EH4 2XU, UK
tional CPC, there will be an educational symposium on functional prob- Tel. +44 (0)131 537 2915 • Fax. +44 (0)131 537 2944
lems in neurology, and a scientific symposium on multiple sclerosis spon- Email. Rustam.Al-Shahi@ed.ac.ukGMC No. 4067993
sored by the MS Society Scotland. On the Thursday evening there will be
Are you attending any Conferences?

Would you like to write a short report for ACNR?
If so, please contact Rachael@acnr.co.uk or call Rachael on 01747 860168 for more information.

Journal Reviews
EDITOR’S CHOICE arrays, they showed that there were significant gene differences in TLX knock
out mice versus a conditional knock out model when the gene was left on.
They then switched neurogenesis off in the brain using this conditional
COGNITION: belief and uncertainty mouse model and showed there was no major changes in the morphology of
the hippocampus and that neurogenesis could still be switched on to some
Is there a neurology correlate to belief? That is, is there a specific extent by physical activities such as running. Furthermore they were able to
region or process that “decides” whether something is true, whether demonstrate that whilst neurogenesis was reduced in these conditional knock
verifiable or not? And is this the same pathway that determines the out mice, there was no change in the fate of neural precursor cells in terms of
belief that something is untrue, or that it is not possible to decide? how many survived and differentiated into neurons. They went on to demon-
Sam Harris and colleagues from the UCLA brain mapping centre strate that there were no deficits in contextural fear learning in contrast to
set out to answer these questions by studying the functional MRI reports from other groups. They did however find major deficits in spatial
activation patterns of 14 healthy people judging written statements learning using a Morris water maze test. They therefore have demonstrated
as “true”, “false” and “undecidable”. These included, amongst oth- that this orphan receptor is critical in the genesis of neurons in the adult hip-
ers, propositions about maths (“1.257 = 32608.5153”), geography pocampus and that this neuronal population seems to be important in spa-
(“California is larger than Rhode Island”), facts (“Eagles are com- tial learning. Of course those cells which do not contain this receptor and
mon pets”) and religion (“A personal God exists, just as the Bible form a separate population may perform some rather different function, but
describes”). The first finding was that subjects were much quicker as to what this is remains a mystery. – RAB
to respond to say a statement was true (3.26 seconds) and slower Han Y-G, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A,
when they thought it was false or were uncertain (3.7 seconds). The Schneider-Maunoury S, Alvarez-Buylla A.
authors like to argue that the brain seems disposed to accept state- Hedgehog signalling and primary cilia are required for the formation of
ments as true, with more neurological “effort” required for disbe- adult neural stem cells.
lief. We are all gullible it seems. NATURE NEUROSCIENCE
When comparing activation patterns of belief versus disbelief (that
2008;11:277-84.
is the belief that something is false), a discrete region of ventrome-
Zhang C-L, Zou Y, He W, Gage FH, Evans RM.
dial prefrontal cortex was found to be associated with belief.
A role for adult TLX-positive neural stem cells in learning and behaviour.
Turning the tables, the left inferior fontal gyrus, anterior insula,
NATURE
dorsal angular cingulate and superior parietal lobules were corre-
2008;451:1004-9.
lated with disbelief. Uncertainty was associated with a positive sig-
nal in the anterior angular cingulate. What to make of all of this?
REHABILITATION: Can you feel me touching you;
Well, firstly it is interesting that different types of belief (mathe-
matical, religious) elicited a similar brain activation, and further in can you feel you touching you?
a region associated with linking factual knowledge to emotions. Despite the importance of sensation for hand function, this aspect of senso-
Perhaps there is a “reward” or “pleasure” in something that is true. rimotor control is a rather neglected area in rehabilitation. Sensory testing of
In contrast, the anterior insula, involved in the disbelief map, is patients with stroke is usually fairly cursory and is limited to determining
associated with perception of pain or disgust. The anterior angular whether a few stimuli are detected. Studies using careful testing procedures
cingulated, activated with uncertainty, is involved in resolving and using a number of different modalities of stimulation have found that up
response conflict. to 65% of stroke patients have impaired somatosensory detection. But detec-
It is easy to overinterpret such imaging studies and cleverer souls tion alone is only part of the picture. In order to be useful, incoming senso-
than I will have to ruminate over the experimental paradigm before ry information must be detected, discriminated and located. A fuller under-
we get too carried away. But, as a scientific romantic, it is hard to standing of impairment in sensory processing is important for developing
resist the conclusion that humans are built to love truth and hate new strategies for rehabilitation.
what is false. Now, where have I heard that before? – AJC Some interesting findings about enhancement of somatosensory perception
Harris S, Sheth SA, Cohen MS. have recently been reported in the JNNP. Valentini et al have analysed senso-
Functional neuroimaging of belief, disbelief, and uncertainty. ry performance in a sample of 39 stroke patients. The patients were tested,
ANNALS OF NEUROLOGY blind-folded, using a Semmes-Weinstein pressure monofilament (a calibrat-
2008 Feb;63(2):141-7. ed nylon fibre attached to the end of a hand held rod). Testing with these fil-
aments allows the pressure to be carefully controlled but also means that the
stimulus is somewhat remote from the hand it is held in. The researchers
compared performance of detection, intensity rating and location when the
NEUROGENESIS: Neural stem cells and behaviour stimuli were applied conventionally by a tester and when the filament was
In Nature Neuroscience the group of Alvarez-Buylla et al have expanded on held in the patient’s unaffected hand. In this latter condition, called ‘self
the observation that Sonic hedgehog is important for the proliferation and touch’, the patient’s hand was positioned and moved by the tester to reduce
maintenance of adult neural stem cells in the subgranular zone in the hip- proprioceptive cueing. A sample of unimpaired control subjects were also
pocampus. They demonstrate that Sonic hedgehog signalling is essential for tested but with a finer filament to avoid ceiling effects. These healthy volun-
expanding the neural precursors in this region during perinatal development teers were able to detect stimulations with a probability of 50-70%.
to establish the adult stem cell population that carries on turning over No advantage of ‘self touch’ was seen in the unimpaired control group.
throughout life. This effect of Sonic hedgehog requires a factor known as However the stroke patient group had significant and reliably improved
Kif3a, which is a subunit of kinesin-II involved with microtubular proteins. detection, intensity estimation and location when the stimuli were delivered
The reason why this is essential for the formation of the stem cell pool is that via the ‘self touch’ method. The effect was found in more than half of the
this protein is important for the motor machinery necessary for assembling patients and in both left and right hemisphere strokes. It was more frequent
primary cilia. If they remove Kif3a, the capacity to make radial astrocytes and in patients with right hemisphere strokes, but no correlation was found
the production of the hippocampal precursors is lost, and thus adult neuro- between the sensory enhancement and visual hemispatial inattention.
genesis fails in this region. Whilst they have no functional data to address The enhanced appreciation for touch could have been due to proprioceptive
what the consequences may be of not having this factor expressed in devel- cueing, but the authors discount this. Their strategy to have the tester move
opment, there is some interesting speculation in this paper about the link the patient’s limb in the self touch condition would only have partially
between certain forms of mental retardation and dysfunctional cilia. reduced the proprioceptive information available, but if the proprioceptive
In a related article in Nature, Zhang et al have explored more explicitly what element was important in enhancing performance surely the effect would
exactly adult neurogenesis is all about in terms of what functions does it serve have been seen in the unimpaired control group too. Instead the authors sug-
in the adult brain. In this paper they have used a series of ingenious strate- gest that the ‘self touch’ enhancement is due to modulation of attention. This
gies with various knock-out mice to investigate what drives neurogenesis. may explain the increased frequency in the right hemisphere patients, how-
They first demonstrate that the orphan nuclear receptor TLX is a marker and ever further investigation with be needed to confirm any attentional mecha-
necessary factor in neural precursor cell proliferation. They demonstrate this nism. Let’s hope the findings will provoke renewed attention from rehabili-
in vitro by showing that knocking out this critical receptor reduces prolifer- tation practitioners and researchers both for improving the quality of senso-
ation by 80%. They then turn to a series of in vivo studies where using micro ry assessments and for testing new ideas for therapy. – AJC

Journal Reviews
Valentini M, Kischka U, Halligan PW. EPILEPSY: How long to treat epilepsy?

Residual haptic sensation following stroke using ipsilateral stimulation. When do you stop AED? In adults the decision is generally made on a mix-
JOURNAL NEUROLOGY, NEUROSURGERY AND PSYCHIATRY ture of medical evidence and social factors; are you going to have a baby or
2008;79:266-70. do you drive for a living? The MRC drug withdrawal study has been the
benchmark used in making decisions regarding AED withdrawal for nearly
NEURODEGENERATION: Progranulin: a promising two decades. This is a smaller study but nevertheless provides up-to-date
growth factor? information, which has both confirmatory and new elements. As a sign of the
The gene, GRN, which codes for progranulin is associated with 17q-linked times, the consent form was drawn up by a legal representative to include
frontotemporal dementia FTD with ubiquitin-immunoreactive inclusions. possible claims from injuries arising as a result of seizures. Patients were
Progranulin is a 593 amino acid glycoprotein containing 7.5 cysteine-rich included after at least two years of seizure-freedom. In fact two thirds had
tandem repeats and is the precursor of granulin proteins. Progranulin is a been seizure-free more than five years and as patients were only on
secreted growth factor found in many tissue types and has been found to be monotherapy, this was a cohort of patients with milder epilepsy than in the
important in development, wound repair, inflammation and tumorgenesis MRC study. Amongst the exclusion criteria were juvenile myoclonic epilepsy
and while it is highly expressed in neurons of the cerebral cortex, its function or a very active EEG in patients with idiopathic generalised epilepsy. One
in the central nervous system is yet to be clarified. Patients with GRN muta- hundred and sixty patients were randomised to either withdrawal or no
tions have variable phenotypes although usually present with frontal variant withdrawal and followed up for a median of 47 months for patients on med-
FTD (fvFTD). Le Ber et al have now carried out a detailed study examining ication and 41 months for patients off medication. Additional data were
the clinical, neuropsychological and brain perfusion characteristics of recorded, including neuropsychological assessment, EEG, quality of life
patients with progranulin mutations to illustrate the highly variable pheno- assessment. Relapse rates in the first twelve months were 7% of those on
types and neuropsychological profiles associated with these mutations and medication and 15% of those withdrawing medication. At the end of the
provide further evidence that clinical phenotype is a poor predictor of the twelve month double-blind period, of the 72 seizure-free patients in the non-
underlying histopathology. withdrawal group, 62 chose to taper medication. This is a surprisingly large
The authors have examined GRN in 502 patients out of which 352 had number and meant that almost as large a cohort stopped medication at the
fvFTD. They have identified 18 mutations of which 7 were novel in 24 fami- end of a year as were randomised to initial withdrawal. Their outcome over
lies including 32 symptomatic mutation carriers. GRN mutations presented the next year was similar. Relapse rate was greatest in the first year after with-
with a variety of phenotypes with again 63% of the carriers having fvFTD drawal and around 80% remained seizure-free at 36 months in both groups.
whilst the remaining 37% had a variety of clinical diagnoses including pri- On an intention to treat basis this means that the two arms are comparable
mary progressive aphasia (PPA), corticobasal degeneration (CBD), dementia but I don’t think it answers the question of whether staying on medication
with Lewy body (DLB) or Alzheimer’s disease (AD). Using DNA extracted carries a lower risk of relapse than coming off it in the longer term, since
from peripheral blood from the 502 patients the authors have looked for from one year onwards more or less the same number in both arms were
deletions of the GRN gene which might be responsible for the partial loss of actually continuing treatment. Numerous factors did not predict seizure-
functional progranulin. After sequencing, it was observed that in patients freedom, including age, gender, partial or generalised epilepsy, MRI, or dura-
with either fvFTD or FTD-MND no mutations were present and further tion of seizure-freedom. A normal neurological examination and seizure
analysis showed no copy number variation. freedom on carbamazepine were associated with a significantly lower risk of
Among the various results presented in this study it is interesting to note that relapse on withdrawal. Since carbamazepine is generally a first-line drug,
Parkinsonism was frequent in the patients (41%), which fits with the obser- those patients on it are likely to have had the easiest to control epilepsy. The
vation of striatal lesions in GRN mutation carriers as well as the presence of patients in this study demonstrated a small but significant improvement in a
visual hallucinations (25%) and motor apraxia (25%), both of which proba- range of neuropsychological tests after drug withdrawal.
bly have an origin in the posterior parietal cortex and supplementary motor So what can one conclude from this study. Firstly, in selected patients with
cortex. Episodic memory disorders were frequent (89%) while results show easy to control epilepsy, drug withdrawal carries only a 20% risk of recur-
that hypoperfusion was observed in the hippocampus, parietal lobes and pos- rence over three years. However, we can’t really say what would happen if the
terior cingulated gyrus and frontotemporal cortices. These results associated patients stayed on the drugs over that time as a comparator. The only thing
with GRN mutations are interesting in the sense that they again show how a we can say is that in the first year the withdrawal group had a relapse risk of
single “genetic” disorder can have a variety of clinical representations and about 15%, compared to 5% in the continuation group. Secondly, withdraw-
pathological profiles. Thus whilst all these mutations are responsible for a al of long term medication in this study (but not all studies) is associated
progranulin haploinsufficiency, there must be other factors that interact with with an improvement in cognitive testing which is difficult to relate to activ-
this to explain the variation of the clinical presentation and pathology. – CA ities of daily living. But the bottom line for the patient asking if their seizures
Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, will come back is only a slightly more educated: “I don’t know.” – MM
Hahn-Barma V, van der Zee J, Clot F, Bakchine S, Puel M, Ghanim M, Erikssen J, Gulbrandsen, P, Gjerstad L.
Lacomblez L, Mikol J, Deramecourt V, Lejeune P, de la Sayette V, Belliard S, Consequences of antiepileptic drug withdrawal: A randomized,
Vercelletto M, Meyrignac C, Van Broeckhoven C, Lambert JC, Verpillat P, double-blind study (Akershus study).
Campion D, Habert MO, Dubois B, Brice A; French research network on EPILEPSIA
FTD/FTD-MND. 2008;49:455-63.
Phenotype variability in progranulin mutation carriers: a clinical, neu-
ropsychological, imaging and genetic study”.
BRAIN
EPILEPSY: Another cause of epileptic confusion
2008:131;732-46. These investigators retrospectively analysed patients in whom continuous
EEG monitoring had indentified thirteen critically ill patients who experi-
enced cyclical seizures with a periodicity of 30 seconds to twenty minutes,
recurring for hours. The patients ranged in age from 12 weeks to 79 years and
Journal reviewers
had a wide range of causes of seizures including hypoxic ischaemic injury,
Heather Angus-Leppan, Royal Free & Barnet Hospitals;
posterior reversible leukoencephalopathy syndrome, Ohtahara syndrome
Chrystalina Antoniades, Cambridge Centre for Brain Repair; and lead poisoning. The mean interseizure interval was 7.6 minutes and the
Roger Barker, Cambridge Centre for Brain Repair; median 6.7 minutes and cycling lasted up to 48 hours with a mean if 7.9
Lloyd Bradley, Colman Centre for Specialist Neurological hours and median 3 hours. Clinical state ranged from confusion to coma.
Rehabilitation Services in Norwich; Interestingly the ictal onset was left sided in 9, diffuse in 2 and right sided in
Alasdair Coles, Cambridge University; 2 patients. Clearly this pattern will only be recognised if there is continuous
Andrew Larner, Walton Centre, Liverpool; EEG monitoring, as in many cases it would be over, before a routine EEG
could be arranged. How many patients have I unknowingly seen with this
Mark Manford, Addenbrooke’s Hospital, Cambridge and Bedford Hospitals;
problem? – MM
Wendy Phillips, Addenbrooke’s Hospital, Cambridge;
Friedman D, Schevon C, Emerson R, Hirsch L.
Robert Redfern, Morriston Hospital, Swansea; Cyclic electrographic seizures in critically ill patients.
Ailie Turton, University of Bristol. EPILEPSIA
2008;49:281-7.

News Review News Review
Special offer to ACNR readers • 15% discount • Offer ends 31 July 2008
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News Review
Elekta chosen to deliver sophisticated brain mapping Elekta chosen to deliver

technology to the Nebraska Medical Center advanced 3-D brain
The Nebraska Medical array has a higher density of mapping technology to
Center will receive its new detectors than any other sys-
Elekta Neuromag® MEG system on the market, leading to
leading French Brain
tem in the spring / summer a more accurate representation Imaging Facility
of 2008. With the MEG of brain activity. The unique
system from Elekta design of the sensors combined
installed, neurosurgeons, with advanced software makes
neurologists and those in it possible to gain data with
related fields will be able to unsurpassed detail, even from
non-invasively record the deepest regions of the
human brain activity in real brain.
time, better and more accu- “The Elektra Neuromag®
rately than ever before. seems ideally suited to helping
MEG technology is us to deal with the most diffi-
regarded as the most effi- cult to treat epilepsy patients,
cient method for tracking many of whom do not respond
brain activity at millisecond well to medications,” said Dr
resolution. Compared to Sanjay Singh, Director of the
EEG technology, MEG has Nebraska Epilepsy Centre.
uniquely accurate localisation capabilities. The For further information please contact
Elekta Neuromag® 306-channel MEG sensor inquiries@elekta.com
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Chelsea and Westminster opts for latest CT non-invasive registration of nerve cell activity
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Chelsea and Westminster Dose Shield, which nology to the new CEA facility - NeuroSpin in
Hospital NHS Foundation blocks unnecessary radi- Saclay, France, one of the largest research
Trust has ordered the newly ation thus ensuring the sites for brain imaging in Europe.
launched SOMATOM patient is only exposed The MEG system will be installed during
Definition AS and AS+ CT to clinically relevant spring of 2008 at the new CEA facility - called
systems from Siemens via dose; a scan length of NeuroSpin - in Saclay which was recently
the NHS Supply Chain up to 200cm and a inaugurated and is planned to soon become
Framework. 78cm gantry opening all the largest European site for brain imaging
The NHS Supply Chain resulting in fast and studies. NeuroSpin will host up to 150
infrastructure is helping to problem-free head-to- research scientists and engineers from CEA
speed up the process of foot scanning. The and INSERM with a large number of visiting
medical equipment procure- Definition AS+ takes groups. The core research staff of NeuroSpin
ment by opening up dia- The SOMATOM Definition AS functionality further, has developed a long history of neuro-imaging
logue between suppliers and combining extremely research on method and instrumentation
Trusts and delivering greater value for money. fast coverage with up to 128 slices per rota- development (notably Position Emission
The SOMATOM Definition AS and AS+ are tion whilst maintaining delivery of crystal-clear Tomography (PET) and fMRI). In addition to
the first CT scanners that adapt to virtually any images, free from movement artefacts and the Elekta Neuromag MEG system, NeuroSpin
patient and clinical need. The systems are showing the finest anatomical details. will host four cutting-edge Magnetic
suitable for routine diagnostic work and com- For more information contact: Siemens, Resonance Imaging (MRI) systems entirely
plex examinations including oncology, neurolo- T. +44 (0)1276 696000, dedicated to neuro-imaging research projects.
gy and cardiology. E. medmarketing.med.gb@siemens.com For further information please contact
The Definition AS combines an Adaptive W. www.siemens.co.uk/medical inquiries@elekta.com
Efficient regional anaesthesia in paediatrics

Dr Steve Roberts, orthopaedic anaes- sometimes don’t respond to the more
thetist at the Alder Hey Hospital in traditional technique of neurostimula-
Liverpool, is using a number of SonoSite tion, so in all of these cases ultrasound
point-of-care ultrasound tools, including makes it much easier to perform the
the SonoSite MicroMaxx® ultrasound blocks successfully.”
system, to perform regional blocks on “There isn’t enough space in our
children of all ages. “The SonoSite sys- anaesthetic rooms for big radiology
tems are used throughout the hospital,” machines, whereas the SonoSite sys-
he explained, “and have saved invaluable tems are really compact. They are very
time, for example, in placing central lines reliable and robust, easy to carry from
in babies. They are especially useful for room to room, and are also less intimi-
some of the children we treat with cere- dating for the patients.”
bral palsy for whom normal anatomical For more information contact:
landmarks just don’t apply because their Sonosite T. +44 (0)1462 444 800,
limbs are quite often deformed. They E. europe@sonosite.com ,
may also have abnormal neurology and W. www.sonosite.com

News Review News Review
New titles from the Royal College of Physicians

Palliative care services: meeting the needs of Long-term neurological conditions
patients Management at the interface between neurol-
This Working Party report focuses on the phi- ogy, rehabilitation and palliative care
losophy of palliative care; the issues facing These guidelines build on the Quality
palliative care; oncological experience and its Requirements in the National Service
application to other diseases; mental health Framework for Long-term (Neurological) also provide practical advice for clinicians
problems in palliative care and the organisa- Conditions (LTNCs) to explore the interaction when caring for someone with an LTNC, as
tion of palliative care and workforce provision. between specialist neurology, rehabilitation well as outlining indications for specialist
The report will be relevant to all doctors and palliative care services, and how they referral.
and allied healthcare professionals and is may best work together to provide long-term For more information and to purchase
essential reading for healthcare planners and support for people with LTNCs and the family copies, T. +44 (0)20 7935 1174 ext 358 or
commissioners of palliative care services. members who care for them. The guidelines visit W. www.rcplondon.ac.uk/pubs
Spire Healthcare selects latest CT & MR imaging equipment for expansion of diagnostic
services
Spire Healthcare, one of the leading independ- high quality definition of bone and soft tissue.
ent hospital providers in the UK, has placed It can adapt to any patient or clinical need in
an order for six MRI and three CT scanners routine diagnostic work and complex examina-
with Siemens as part of the drive to expand tions in cardiology, neurology and oncology.
its range of diagnostic imaging services. Six MAGNETOM Avanto 1.5T MRIs will also
The order includes three SOMATOM be delivered to Spire Healthcare sites. The
Definition AS CT scanners, the first of which systems will provide detailed image results to
will be installed at Spire Norwich Hospital, a enable a flexible approach to examination pro-
BUPA-accredited bowel cancer centre of excel- cedures.
lence that also specialises in orthopaedic sur- For more information contact: Siemens
gery. The CT scanner has a unique Adaptive T. +44 (0)1276 696000,
Dose Shield that blocks unnecessary radiation cally relevant dose. It produces clear images E. medmarketing.med.gb@siemens.com
ensuring the patient is only exposed to a clini- whilst eliminating spiral artifacts, ensuring W. www.siemens.co.uk/medical
Awards and Appointments
New Director of the Institute of Neurology appointed

Professor Alan Thompson has been appointed to the position of mechanisms that underlie disability in neurological
tion of Director of the Institute of Neurology. He took up conditions, particularly multiple sclerosis, the development
his new role on 1st April 2008, taking over from Professor of outcome measures which assess the impact of such
Lemon who directed the Institute of Neurology for almost conditions and the improvement of symptomatic manage-
six years. Professor Thompson received his undergraduate ment and service delivery in MS.
and postgraduate degrees from Trinity College Dublin, and Ed Byrne, Dean of the Faculty of Biomedical Sciences
is the Garfield Weston Professor of Clinical Neurology and and Head of the Medical School said, “We send our hearty
Neurorehabilitation at the Institute of Neurology, where he congratulations to Professor Thompson and our warmest
is head of the Research Department of Brain Repair and thanks to Professor Lemon for contributions past, present
Rehabilitation. His research interests include the investiga- and future.”
Doctors awarded grant from Ataxia UK MS Society Award Grants for project
Dr Andrea Nemeth and Dr Kevin Talbot have been awarded a grant Heidi Johansen-Berg, Margaret Esiri, Jackie
from Ataxia UK to develop high throughput genetic testing for patients Palace, Karla Miller and Steven Chance
with ataxia and related disorders. Each of the many forms of inherited have been awarded a one-year grant for
ataxia is individually rare and, in common with other neurogenetic dis- £136,000 from the MS Society. The proj-
orders, screening of multiple individual genes is time-consuming, labo- ect is entitled ‘Feasibility study for MRI and
rious and expensive. Therefore, most patients do not have a formal neuropathological investigations of the role
molecular diagnosis and this also hampers research efforts and clinical of anatomical connections in determining
trials. patterns of neurodegeneration in MS’. The project will
This grant will allow them to utilise some of the resources which are help set up collaborative post-mortem imaging and histological
being developed as part of the Biomedical Research Centre for transla- studies of MS and healthy human brains and will provide funds for a
tional research to develop a high throughput approach to genetic testing. post-doctoral physicist, image analyst and neuroimaging/pathology
The aim is to work towards providing a national service in this area. researcher.
We’d love to hear your Award and Appointment news. Please send submissions to Anna Phelps
Email: anna@phelps1972.freeserve.co.uk

07-9241_Master Ad v2 AW:Layout 2 19/10/07 15:16 Page 1
COPAXONE® (glatiramer acetate)

PRE-FILLED SYRINGE
PRESCRIBING INFORMATION
Your decision
today
Presentation - Glatiramer acetate 20mg
solution for injection in 1ml Pre-filled Syringe.
Indication - Reduction of frequency of
relapses in relapsing-remitting multiple
sclerosis in ambulatory patients who have had
at least two relapses in the preceding two
years before initiation of therapy. Dosage and
administration - 20mg of glatiramer acetate
(one pre-filled syringe) administered sub- can make a difference
tomorrow
cutaneously once daily. Children (<18 years)
Not recommended. Elderly No specific data.
Impaired renal function No specific studies.
Monitor renal function during treatment and
consider possibility of deposition of immune
complexes. Contra-indications - Known
allergy to glatiramer acetate or mannitol
(excipient). Pregnancy. Special warnings and
precautions - Sub-cutaneous use only.
Initiation to be supervised by neurologist or
experienced physician. Supervise first self-
injection and for 30 minutes after. One or
more of vasodilatation, chest pain, dyspnoea,
palpitations or tachycardia may occur within
minutes after injection. These generally
resolve spontaneously after a short time. If
severe, treat symptomatically. Caution in
patients with pre-existing cardiac disorders
and review such patients regularly. Rarely
convulsions and/or anaphylactic or
allergic reactions. Rarely, hypersensitivity
(bronchospasm, anaphylaxis or urticaria). If
severe, treat appropriately and discontinue
Copaxone. Interactions - No formal
evaluation. Increased incidence of injection-
site reactions with concurrent corticosteroids.
Theoretical potential to affect distribution of
protein-bound drugs, therefore concomitant
use of these should be monitored. Pregnancy
and lactation - Not to be used in pregnancy.
Consider contraceptive cover. No data on
excretion in human milk. Undesirable effects
- Injection site reactions (erythema, pain,
mass, pruritus, oedema, inflammation,
hypersensitivity, lipoatrophy). An immediate
post-injection reaction (one or more of
vasodilation, chest pain, dyspnoea, palpitation,
tachycardia) may occur within minutes,
reported at least once by 41% of patients
receiving Copaxone compared to 20% of
patients receiving placebo. >1%: Nausea,
anxiety, rash, sweating, chills, face oedema,
syncope, vomiting, lymphadenopathy, oedema,
nervousness, tremor, herpes simplex, skin
benign neoplasm, eye disorder, vaginal
moniliasis. Rarely: Anaphylactoid reactions,
convulsions, shifts in white blood cell counts,
elevated liver enzymes (with no evidence of
clinical significance) and skin necrosis at
injection sites. Please refer to the SPC for a
full list of adverse events. Overdose - Monitor,
treat symptomatically. Pharmaceutical
Precautions - Store Copaxone in refrigerator
(2ºC to 8ºC). If the pre-filled syringes cannot
be stored in a refrigerator, they can be stored
at room temperature (15ºC to 25ºC) once for
up to one month. Legal Category - POM.
Package Quantity and Basic NHS Cost - 28
pre-filled syringes of Copaxone: £545.59.
Product Licence Number - 10921/0023.
Further Information - Further medical
information available on request from Teva
Pharmaceuticals Limited, The Gate House,
Gatehouse Way, Aylesbury, Bucks, HP19 8DB
Date of Preparation - September 2007.
Information about adverse event

reporting can be found at
www.yellowcard.gov.uk.
Adverse events should also be reported to
Teva Pharmaceuticals Ltd on
telephone number: 01296 719768.
Reference: Ford C. et al. Multiple Sclerosis 2006; 12: 309-320.
(glatiramer acetate)
Long-term active
Date of preparation: October 2007 Code: C0807/428a

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ISSN 1473-9348 Volume 8 Issue 2 May/June 2008

Advances in Clinical Neuroscience & Rehabilitation

Declan Chard and David Miller

Reuben Johnson and Hilary Madder

Conference News • Journal Reviews • Book Reviews • Diary of Events

Editorial board and contributors

ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I3

ISSN 1473-9348 Volume 8 Issue 2 May/June 2008

Advertising and Editorial: Patricia McDonnell

Advances in Clinical Neuroscience & Rehabilitation

Tel/Fax: 0288 289 7023

Declan Chard and David Miller

4 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

KEPP7032 ADV CNR.indd 1 19/12/07 16:54:39

The Neurological Sleep Clinic – Part 2

6 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

ACNR free on-line

Read ACNR www.acnr.co.uk

Advances in Clinical Neuroscience & Rehabilitation

You can read every issue of ACNR free of charge

Maurice Curtis, Andrew Naylor, Richard Faull

Reuben Johnson and Hilary Madder

Emma Matthews, Mike Hanna

Are you organising an event,

Would you like to review a book,

T/F. +44 (0)288 289 7023 John Stein

E. Sales@acnr.co.uk Phil Cowen

Conference News • Journal Reviews • Book Reviews • Diary of Events

ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I7

Magnetic Resonance Imaging in Multiple Sclerosis –

8 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

Table 2: McDonald criteria (2005) for establishing a diagnosis of MS.

Two of the following:

intracranial volumes; this adjustment yields

ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I9

ACNR Book Competition

Essential to the management of patients suffering from neurological disorders is an understanding of

10 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

The chance to control seizures, not lives

The Ethical Challenge Posed by Acquired Brain Injury

12 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

When he needs Parkinson’s disease treatment day and night…

Information about adverse event reporting can be found at www.yellowcard.gov.uk

Evoked Potentials and the Prognosis of Comatose Patients

W diction on an individual patient basis during

14 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

Brain Vision V-Amp (Brain Products GmbH)

EasyCap Active (EasyCap.de)

Brain Vision V-amp

BrainVision UK Ltd was established in 2004. We are a For more information

ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I 15

The Significance of Diffuse Axonal Injury:

16 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008

Table 4: The role and significance of Amyloid Precursor Protein (APP).

Amyloid precursor protein (APP)

ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008 I 17

18 I ACNR • VOLUME 8 NUMBER 2 • MAY/JUNE 2008